An Uphill Struggle for the New Super Painkiller
Opponents of the experimental 100% hydrocodone drug won a major battle over pain patients at the FDA last Friday. But will they win the war—and stop a potential new opiate epidemic?
New York Senator Charles Schumer calls it a “powerful super drug…[that would] instantly become the most sought-after drug by addicts and criminals." The media has dubbed it a “super painkiller.” Lewis Nelson, a toxicologist at New York University’s Langone Medical Center, says that it “has the potential to be OxyContin all over again.” And last Friday, an FDA's advisory committee resoundingly voted against its approval.
What is it? Commercially known as Zohydro ER, it is pure, extended-release hydrocodone. Vicodin, the best-selling hydrocodone-based drug, is not “pure” as it also contains acetaminophen. Currently, both OxyContin and Vicodin have the dubious distinctions of being the nation's first- and second-most abused prescription drugs, respectively. And Zohydro, the new “super drug,” has up to 10 times more hydrocodone than Vicodin.
The FDA is expected to make a final decision about whether to OK Zohydro for market by March, after considering the advisory committee’s stance. Zogenix, the company that makes Zohydro, meanwhile, stands to make up to $500 million in annual sales from its baby over the next few years according to Wall Street analysts. (It will lose even more in development costs if the drug is dumped for good.) Until then, the outcry—which contends that the experimental painkiller is unnecessarily strong and just plain unnecessary—is likely to continue.
The headlines say it all: “Schumer Warns Of ‘Super Drug’ 10X More Powerful Than Vicodin”; “Warnings Over New Painkiller ‘Super Drug’”; “Schumer Rails Against FDA Testing Of Super-Potent Painkillers.” But what the headlines almost never get right is that Zohydro is a slow-release formulation. Thus, although Zohydro is 10 times stronger than the lowest dose of Vicodin—not the highest—it also lasts about four times longer. Its 12-hour duration is Zohydro’s added value to the painkiller market. A drug that releases its active ingredient over 12 hours is necessarily stronger than a drug like Vicodin, which only lasts three to four hours.
Zohydro offers addicts a dose of purer hydrocodone—and more of it—than they have ever had access to before.
The problem is that its “extended release” is effective only when taken as prescribed. If crushed and snorted (or dissolved and injected), the effect is immediate. So Zohydro offers addicts, would-be addicts, and wily or just unsuspecting teenagers a dose of purer hydrocodone—and more of it—than they have ever had access to before. In other words, one of the most widely abused drugs of all time now comes in a more potent form—arguably, that makes it unnecessarily strong.
Whether Zohydro is necessary is a trickier question. “I have a big concern that this could be the next OxyContin. We just don’t need this on the market,” says April Rovero, president of the National Coalition Against Prescription Drug Abuse. But the danger of potential abuse must be weighed against proponents' claim that it provides a much-needed benefit for many pain patients. Zohydro’s 12-hour longevity, they say, is an effective way for chronic pain sufferers to avoid taking multiple doses throughout the day—and to avoid having to wake up at night to dose. Plus, because Zohydro does not contain acetaminophen, it is easier on the liver than Vicodin, which for long-term users is a big boon. But as one FDA advisory panelist pointed out last Friday, it isn’t clear how big the acetaminophen-intolerance patient numbers really are.
Most members of the FDA advisory panel were doubtful that the benefit to this narrow cohort of pain-sufferers is worth the risk of abuse. The drug's potential long-term side effects, particularly on neurological function, were also questioned, and the panel dismissed Zogenix’s 12-week studies as much too short to settle this question. If approved, Zohydro will likely be prescribed—at least officially—to manage chronic pain (as opposed to the acute, immediate pain that comes after, say, surgery). "Zohydro will probably be a lifetime prescription,” said one advisory panelist. "There is currently no long-term understanding of efficacy.…Are we doing more harm than good?”
An even bigger problem with Zohydro is that—regardless of strength or necessity—it is almost absurdly easy to abuse. Zogenix has no plans to make the drug crush proof. Given that the only other extended-release opioid, OxyContin ER, saw significant drops in rates of abuse after the capsules were made tamper-resistant—all without decreasing its effectiveness—it seems a no-brainer that Zogenix should have developed an abuse-resistant Zohydro. In the face of the media frenzy over the so-called Oxy Epidemic, what were they thinking?
One reason that they didn't is that they didn’t have to. Currently the FDA's risk-management measures for painkillers do not require tamper-proof formulations. Thus, Zogenix is in compliance with FDA safety strategies—which essentially amount to zealous education efforts for clinicians and patients—while still marketing a 50 mg hydrocodone pill that can be snorted or shot up. “[The FDA's risk-management measures] educate parents, not thieves,” one advisory panelist said.
Zogenix asserts that tamper-resistant formulations have “issues,” citing only a list of boilerplate problems associated with many common drugs. For example, the company says that crush-proof formulations include risks of “choking” and “intestinal obstruction" linked to OxyContin ER—but neither prevented that drug from coming to market.
Zohydro may become the drug of choice among opiate addicts, attracting many who switched to heroin following the advent of tamper-proof oxy.
Zogenix also claims that tamper-resistant versions diminish efficacy. I asked a Zogenix rep for evidence to support that claim. Rather than offering data from a clinical study of hydrocodone, the firm steered me to anecdotes reported on a Phoenix, Arizona, TV news affiliate website—about the diminished effects of tamper-proof OxyContin ER. Yet in the same article, James Heins, a rep for Purdue Pharma, the maker of OxyContin, says that its abuse-proof formulation is “bioequivalent to the original version” and “performs similarly to the original version.”
Further, although it’s no secret that hydrocodone is addictive, it may in fact be even more addictive than originally thought. There is a widespread perception that because current hydrocodone painkillers (which are all combined with acetaminophen) are Schedule III drugs, they are less dangerous than oxycodone painkillers, which are Schedule II. (The difference turns on potential for abuse, with II indicating high abuse and III indicating moderate.)
But Dr. Sharon Walsh of the Center for Drug and Alcohol Research at the University of Kentucky presented data at the FDA hearing showing that current drugs with hydrocodone are milligram for milligram only slightly less potent than oxycodone (0.93 mg. of oxy is equal to 1 mg. of hydro). This finding would seem to argue that the two narcotics have the same controlled-substance designation. Further, because Zohydro lacks acetaminophen, its potency may indeed be on a par with oxycodone's.
Zohydro ER, if approved, will be slapped with a Schedule II label in recognition of its potency and addictiveness. Its extended-release formulation warrants maximum vigilance. Information from Drug Abuse Warning Network, presented by Rajdeep Gill of the FDA epidemiology department, shows that the abuse ratio for single-ingredient, extended-release oxycodone products is three to four times higher than combination-oxycodone products. As a result, Zohydro stands a good chance of becoming the drug of choice among opiate addicts, attracting many who have had to switch to heroin following the advent of tamper-proof oxy. In this way, Zohydro risks reversing the sharp decline of oxy addiction and overdoses seen in recent years.
While the advisory committee’s vote against approval is only a recommendation, the FDA rarely goes against its own handpicked advisors.
For now, Zohydro's prospects of making it to market in 2013 are not encouraging. While the advisory committee’s 11-to-2 vote against approval is only a recommendation, the FDA rarely goes against its own handpicked advisors.
Still, the meeting did not lack calls by officials and advocates to give Zohydro a hearing unbiased by the dark legacy of OxyContin. Dr. Bob Rappaport, director of anesthesia, analgesia and addiction products at the FDA, admonished the panelists to distinguish between Zohydro and other opiates lest they be seen as “punishing this company and this drug because of the sins of other companies and their product." In addition, pain patients and their advocates reminded the FDA advisors of the relatively low incidence of addiction among prescription users with chronic pain.
Yet this case for alevel playing field gained little traction given the threat posed by Zohydro ER of a new "oxy epidemic." As one advisor put it, approving a new opioid without tamper resistance would be opening a public health “Pandora’s Box.”
Sacha Z. Scoblic is the science writer at The Fix, the author of Unwasted and a Carter fellow for mental health journalism.