Abuse and misuse of prescription drug painkillers is soaring, responsible for more than 16,500 deaths in 2010, according to
the Centers for Disease Control and Prevention (CDC). More than 250 million opioid prescriptions were filled in 2009, fueling
a $9 billion market. Limiting opioid abuse is the most crucial public health issue for the Center for Drug Evaluation and
Research (CDER) at FDA, said CDER Deputy Director Douglas Throckmorton in December 2012 at an industry conference. FDA seeks
stronger warning labels and is encouraging development of abuse-deterrent formulations of long-acting opioids. Yet, Throckmorton
notes the challenge of assuring patient access to these crucial drugs while reducing the “epidemic of abuse and misuse.” This
dilemma reflects a split in the medical community: pain specialists plead for ready access to needed medications for more
than 100 million adults with chronic pain, while a growing number of experts back curbs on prescribing to curtail abuse. A
key question is whether long-term treatment with opioids for pain is safe and effective, compared to use of these drugs for
The opioid crisis also has drawn attention of Congressional leaders. The Senate Finance Committee launched an investigation
in May 2012 of financial ties between opioid manufacturers and pain experts, looking for links between pharma industry money
and the surge in inappropriate drug use. Sen. Joe Manchin (D-WV) sought to add stronger controls on certain opioids to last
year’s FDA Safety and Innovation Act (FDASIA), but backed off when FDA promised to address the issue this year. The development
of new opioids with anti-abuse features also is spurring legislative proposals to block generic versions of older, easily
Push for controls
FDA’s immediate task is to weigh the scientific and medical merits of a proposal from the Drug Enforcement Administration
(DEA) to impose stricter controls on drugs such as Vicodin (combination of hydrocodone and acetaminophen). DEA initially petitioned
FDA in 2004 to evaluate evidence for reclassifying hydrocodone combination products from schedule III to schedule II under
the Controlled Substances Act (CSA). This “upscheduling” would impose more stringent recordkeeping and storage requirements
on 81 marketed combination medicines, virtually all of which are generic drugs. Schedule II prescriptions cannot be refilled
or phoned in by doctors, and nurse practitioners and physician’s assistants can’t write scripts. The fear is that going to
the doctor every three months for a new prescription could over-burden individuals who are coping with chronic pain.
FDA rejected DEA’s initial proposal, questioning whether the schedule change would make a real difference, considering the
rampant abuse of opioids such as OxyContin and morphine that already are schedule II. DEA has come back with additional data
on the surge in opioid-related deaths and hospitalizations, which has generated a groundswell for action. FDA sought advice
on DEA’s proposal from its Drug Safety and Risk Management Advisory Committee at a January 2013 meeting (rescheduled from
October 2012 due to Hurricane Sandy). FDA safety experts and representatives of medical organizations analyzed DEA’s research,
while dozens of family members and medical practitioners described their experiences with drug-induced deaths and ruined lives.
Opposition to DEA’s proposal came from the Generic Pharmaceutical Association (GPhA), which predicted supply-chain problems
as manufacturers and wholesalers face requirements for larger vaults and new systems for storing controlled ingredients and
finished goods. Pharmacists complained about a host of costly new security procedures, while practitioners predicted access
problems for patients suffering from cancer, trauma, and post-operative pain. Despite FDA skepticism about the policy change,
the advisory committee voted 19-10 in favor of DEA upscheduling, and FDA is expected to follow the panel’s advice.
These issues were re-examined a week later at a February FDA public hearing on proposals to add stronger labeling and warnings
on opioid painkillers. Physicians for Responsible Opioid Prescribing had petitioned FDA to revise labels to limit opioid treatment
to 90 days and to patients with “severe” and not “moderate” pain. Again, dozens of stakeholders testified on abuse and access
issues. Family members of addicts complained that existing labels fail to adequately inform doctors or patients of the severe
risks of the drugs; pain specialists opposed arbitrary limits, emphasizing the need for flexibility to treat patients based
on individual needs. There was discussion about whether a drug track-and-trace system, using serialization to identify individual
units, could curb illegal opioid distribution. Pharmacists supported this approach, along with use of electronic medical records
and drug monitoring programs to identify dangerous drug use.
Another strategy for curbing opioid abuse is for manufacturers to develop extended-release pain medications that resist tampering
and misuse. FDA issued draft guidance in January 2013 that advises manufacturers on the types of studies needed to demonstrate
anti-abuse effectiveness and explains how the agency will evaluate safety data and approve labeling for such products (1).
The document describes how data could support a range of claims in labeling: that a product provides a barrier to abuse, blocks
opioid effect when manipulated, leads to meaningful reduction in abuse, or demonstrates reduced abuse in the community.
The success of newer, tamper-resistant products, however, raises a much trickier issue for FDA: whether to block generic copies
of earlier opioids that are more easily abused. Perdue Pharma gained approval in 2010 for a reformulated version of OxyContin
that was more difficult to crush or dissolve and now wants FDA to rule out generic versions of its original product. Endo
Pharmaceuticals has sought similar protection for an improved version of Opana.
Commissioner Hamburg clarified in a January letter to Congressional leaders that FDA has authority to require generic opioids
to adopt new tamper-resistant formulations, but only if the agency determines that such newer products will “significantly
deter abuse”, which FDA has yet to do (2). Hamburg hopes to head off legislation that would block FDA approval of generic
versions of abuse-prone medicines, but recognizes that brand manufacturers are unlikely to develop new tamper-resistant products
if cheaper versions of old drugs come to market.
At the same time, manufacturers may find it difficult to gain FDA approval of new painkillers without anti-abuse features,
as seen in delayed action on approving Zohydro, a high-dose, long-acting hydrocodone product from San Diego-based Zogenix.
An advisory committee rejected the drug last December, expressing fears that Zohydro could lead to dependence and would be
highly attractive to illicit users.
Meanwhile, FDA is being more proactive in the war against opioid abuse. It’s promoting prescriber and patient education on
appropriate drug use, and agency scientists are working with academics on research methods for assessing opioid effectiveness
and innovative package designs that may deter misuse.
Public officials also are taking action. New York City Mayor Michael Bloomburg announced in January that city emergency rooms
would provide only three-day supplies of opioid painkillers to patients (3). Hospitals in Utah, Michigan, and Wisconsin are
reducing or eliminating opioids from emergency rooms in favor of non-narcotic medications. Yet, a tough anti-abuse law in
Kentucky is headed for revision because it created access problems for seriously ill patients.
State attorneys general (AGs) also weighed in recently, calling on FDA to require generics makers to produce tamper-resistant
versions of opioid medicines. In a letter to commissioner Hamburg March 11, 2013, 48 AGs raised concerns that illegal users
are shifting to older, more easily abused products as the newer formulations come to market (4). Regulation and production
of dangerous, but clinically important, drugs is not simple from any perspective.
1. Draft guidance on Abuse-Deterrent opioids – evaluation and labeling, available at www.fda.gov.
2. M. Hamburg, Letter to House Energy and Commerce Committee chairman Fred Upton (Jan. 8, 2013).
3. Press Release, “Mayor Bloomberg, Deputy Mayor Gibbs and Chief Policy Advisor Feinblatt Announce New Emergency Room Guidelines
to Prevent Opioid Prescription Painkiller Abuse,” New York Times, Jan. 10, 2013.
4. K. Palmer, “Forty-Eight State and Territorial Attorneys General Call for Tamper-Resistant Versions of Generic Prescription
Pain Killers’” http://www.fdalawblog.net, accessed Mar. 12, 2013.