Last year, the Food and Drug Administration (FDA) approved an opioid pain relief drug called Zohydro. Zohydro is an extended-release drug that contains pure hydrocodone—the main ingredient in the painkiller Vicodin. Supporters of the approval believe the drug can be a useful alternative to treating patients with chronic pain because, unlike hydrocodone combination products, Zohydro lacks acetaminophen, which can cause liver damage.
The FDA approved Zohydro over the recommendation of its advisory board, and the decision has since received serious backlash. Five northeast governors have asked that the approval be rescinded due to the drug's high potential for abuse. In September, several anti-addiction groups asked for FDA-commissioner Margaret Hamburg’s resignation. Now, the FDA has responded to these complaints in an article in the Journal of the American Medical Association.
What is Zohydro?
Zohydro is the only painkiller to contain nothing but hydrocodone, the active ingredient. As noted above, other hydrocodone combination products can contain acetaminophen. When taken in large doses as people in chronic pain often require, acetaminophen can cause liver damage. Also unique to Zohydro is that it is an extended-release drug, which means that it works over a long period of time and can contain 5-10 times as much active opioid as Vicodin. FDA describes Zohydro as suited to treat “pain severe enough to require daily, around-the-clock, long-term treatment and for which alternative treatment options are inadequate.”
Zohydro Sparks Controversy
In a letter to HHS Secretary Sylvia Burwell, 15 anti-addiction groups stated: "We are especially frustrated by the FDA's continued approval of new, dangerous, high-dose opioid analgesics that are fueling high rates of addiction and overdose deaths." (See FiercePhrma). They argue that certain opioids, while designed for cancer patients and end-of-life-care, are in many cases prescribed for back pain.
Another major complaint listed against Zohydro is that while the drug is designed to be released slowly over a 12-hour period, it doesn’t have abuse-deterrent features of other opioids. Zohydro consists of capsules containing small, white, bead-like particles of hydrocodone. They “can be crushed, chewed or mixed with alcohol to provide a kick,” Wall Street Journal’s Pharmalot reports. Abuse-deterrents might include agents that make snorting of the medication unpleasant or agents that turn a pill into a gel if heated, which would make it impossible to inject. (Read FDA's analysis of a recent abuse-deterrent feature here; view FDA's abuse-deterrent opioid guidance here)
The negative press around the drug also seems to have resulted from Zohydro’s coming out at a time when increased political emphasis is being placed on how to prevent prescription drug abuse. Amidst a number of well-publicized overdoses and staggering prescription drug abuse figures, bringing a new opioid to market, even with specific benefits to needy populations, runs counter to the dialogue of what has become a national crisis.
We recently wrote about the DEA’s decision to move hydrocodone combination products like Vicodin from Schedule III into Schedule II. The DEA’s stated purpose of the change to a more restrictive schedule was to minimize the misuse of the drugs for recreational purposes while still ensuring that patients with severe pain have reasonable access to the amount of drug needed to control their pain and suffering. “Almost seven million Americans abuse controlled-substance prescription medications, including opioid painkillers, resulting in more deaths from prescription drug overdoses than auto accidents,” said DEA Administrator Michele Leonhart. “[This] action recognizes that these products are some of the most addictive and potentially dangerous prescription medications available.”
In support of the schedule change, the State Attorney General and a U.S. Senator from West Virginia, the state with last year's highest per capita rate of prescription drug overdose in the nation, wrote in strong support of rescheduling: “It will help prevent these highly addictive drugs from getting into the wrong hands and devastating families and communities. I urge the DEA to move quickly in finalizing its regulations so that we are able to save hundreds of thousands of lives."
Clearly, this is not an ideal political environment to introduce a powerful new opioid.
The FDA believes, however, that singling out FDA’s approval of Zohydro is not the best way to combat prescription drug abuse.
In testimony before a Senate committee earlier this year, Margaret Hamburg said, "[w]e recognize that this is a powerful drug, but we also believe that if appropriately used, it serves an important and unique niche with respect to pain medication and it meets the standards for safety and efficacy." The FDA has also approved some drugs that are formulated in ways to make them more difficult to abuse, but Hamburg has acknowledged that abuse-deterrent technology so far has been unable to foil dedicated abusers.
In their article in the Journal of the American Medical Association, Christopher M. Jones, PharmD, MPH, and Peter Lurie, MD, MPH, of FDA, as well as Janet Woodcock, MD of CDER, responded to the negative backlash this drug has been receiving. These authors wrote that Zohydro met all of the standards necessary for approval, including safety standards, quoting the committee chair in saying, “it is my view that the committee felt most strongly, first, that the sponsor met the requirements [for approval] that they were asked to meet.”
They go on to say that the committee recommended a Risk Evaluation and Mitigation Strategy (REMS) to go along with the approval of the drug. This REMS includes training on the appropriate use of opioids and development of an abuse-deterrent form of Zohydro.
More significantly, however, the authors emphasize that focusing on one drug—Zohydro—is going to have little positive effect on the efforts to combat opioid abuse. “The risk in singling out a single drug like Zohydro ER in this complex, multidrug epidemic is that resulting policy is unlikely to have an effect on the underlying causes—the abuse of multiple opioids and other drugs and inappropriate prescribing.”
According to FDA and CDER, almost every instance of opioid abuse and overdose are “polysubstance,” meaning that more than one opioid is being abused by the same person at the same time. Additionally, FDA cites inappropriate opioid prescribing “as a major contributor to the increase in morbidity and mortality.”
The FDA’s response goes on to list several more important and effective means of combating opioid abuse that do not necessitate the banning of Zohydro. They referenced Florida’s “comprehensive strategy [that included] enacting a pain clinic law that mandated physician-owned clinics, required that clinics be registered with the state, and prohibited office-based dispensing of Schedule II and III drugs; prescription drug monitoring program implementation; and enforcement actions against clinicians prescribing opioids outside the usual course of professional practice.”
This strategy is cited as producing a 27% decline in the opioid overdose death rate within that state.
Finally, the authors described current steps the agency is already taking to curb opioid abuse. First, they have recommended that hydrocodone combination products be moved from Schedule III to Schedule II under the controlled substance act, as we noted above. Second, the agency has worked to create steps to facilitate the development of abuse-deterrent versions of drugs. Third, the FDA is working to incentivize the development of nonopioid pain medication in an attempt to reduce overall dependence on opioids.
The FDA concluded their response by saying, “[p]olicies that focus on a single drug can divert focus from broader, further-reaching interventions, such as maximizing prescription drug monitoring programs, leveraging insurer strategies, improving clinician education and oversight, and expanding access to medication-assisted treatment for opioid addiction. The concerns over Zohydro ER should be seen in the greater context of the opioid epidemic. Singling out one drug for restrictions is not likely to be successful.”