Safety Plan for Opioids Meets Resistance

As deaths from unintentional overdose with opioid drugs continue to increase, a plan proposed by the drugs' makers to curb opioid-related deaths and injuries has provoked controversy.

In February 2009, the US Food and Drug Administration (FDA) announced that it was requiring manufacturers of extended-release and long-acting opioids to work together to develop a plan to reduce unintentional overdoses in patients taking these products. The agency proceeded to meet with industry and other stakeholder groups to gather feedback, and at a meeting in early December, an industry working group presented a proposal calling for additional training for opioid prescribers and improvements to materials containing patient safety information. But the proposal has met resistance from health care worker organizations and other groups, which argue that mandatory physician training would ultimately limit patient access to pain medication.

In response to such criticism, the industry working group proposed a phased implementation in which prescriber training is initially voluntary. However, FDA officials at the meeting criticized the phased approach, saying it is nearly identical to the existing safety plans for these drugs and does too little to address the pressing safety concerns surrounding the products.

“There are significant and serious ongoing safety concerns with the use of these products that need to be addressed,” said John K. Jenkins, MD, director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research during a press briefing after the meeting. “We need to ensure safe use while providing access.”

The number of fatal poisonings involving opioid drugs more than tripled between 1999 and 2006, from about 4000 to 13 800 deaths, according to statistics released in September by the US Centers for Disease Control and Prevention's National Center for Health Statistics (NCHS; http://www.cdc.gov/nchs/data/databriefs/db22.pdf).

The reasons for this dramatic increase are not clear, said Margaret Warner, PhD, an injury epidemiologist at the NCHS, during a briefing about the report. In particular, Warner explained, the data do not specify whether the individuals who died obtained the drugs by prescription or illegally.

But the data do provide some information that may offer clues for researchers and public health authorities. For example, poisoning deaths involving methadone increased more rapidly than deaths from other opioids, growing nearly sevenfold from 790 in 1999 to 5420 in 2006. Although methadone has been used successfully as a treatment for opioid addiction for more than 40 years, it has more recently become widely used for pain management under far less strict controls than those required of substance abuse treatment facilities. Additionally, methadone is a long-acting opioid that requires careful dosing. The drug relieves pain for several hours, but may remain in the body for days. Warner explained that a patient may decide to take another methadone dose when the pain relief wears off, and over several days or weeks, a toxic dose of methadone may build up in the body.

Additionally, the rates of opioid poisoning deaths varied widely among states, from 1.8 to 15.6 deaths per 100 000 population in 2006. Among the states with the highest rates were West Virginia, Utah, New Mexico, Oklahoma, and Nevada.

Diversion may contribute to many such deaths in some areas. One 2008 study of unintentional medication overdoses in West Virginia between 1999 and 2004 found that more than 90% (275 individuals) of the 295 deaths were caused by opioid analgesics, but fewer than half of these individuals had ever been prescribed these drugs (Hall AJ et al. JAMA. 2008;300[22]:2613-2620). Of these opioid analgesic–related deaths, 227 involved a Schedule II opioid.

Warner also said the deaths related to opioids were likely “just the tip of the iceberg.” She noted that the NCHS study did not examine emergency department visits, hospitalizations, or other nonfatal injuries associated with inappropriate use of these products.

A key element of the industry working group's initial proposal was a requirement that physicians and other prescribers undergo training on the appropriate use of long-acting and sustained-release opioid products as a prerequisite to receiving a Schedule II prescribing license from the Drug Enforcement Agency. The working group comprised representatives from more than 20 companies, including Johnson & Johnson, Ortho-McNeil-Janssen Pharmaceuticals, Inc, Purdue Pharma LP, and Teva Pharmaceutical Industries LTD, that produce long-acting or sustained-release drugs containing fentanyl, hydromorphone, methadone, morphine, oxycodone, or oxymorphone.

The working group recommended that the prescriber training should be available in a variety of formats, including online; be created by professional societies with input from the FDA and industry; and count as continuing medical education (CME) credit. The training should address such issues as proper patient selection (typically patients with chronic pain who are opioid tolerant), proper dosing, identifying or preventing substance abuse, special instructions for select populations, and ways to educate patients about safe use, storage, and disposal.

The plan also proposed that both the patient and clinician sign an agreement detailing their respective responsibilities to ensure safe use. Additionally, it called for manufacturers to produce 18 new patient medication guides for the products.

The industry working group invited various stakeholders to a meeting November 18. There, many individuals and groups expressed concern that an onerous certification process would cause some physicians to stop prescribing the products, which in turn would reduce patient access, particularly in medically underserved communities, said Susan Nicholson, MD, a working group representative from Johnson & Johnson. In response to the criticism, Nicholson and other working group representatives suggested a phased approach, in which prescriber certification would initially be voluntary and the results closely monitored to ensure no ill effects from legitimate prescribing.

But FDA representatives at the meeting criticized the revision, saying that without a mandatory prescriber certification program, the proposal offers little improvement over existing safety plans for the drugs. Jenkins explained during the press briefing that if the training were voluntary, many clinicians might decline, and it would be difficult to track who is trained.

“DEA [Drug Enforcement Administration] registration is optimum, but even then some physicians may opt out,” Jenkins said. He acknowledged that this may limit access in certain areas.

There are other barriers as well, he noted. Congress would have to pass legislation giving the DEA authority to link licensing to prescriber certification. Such a legislative effort may take considerable time and may face resistance from medical organizations and others who oppose such a mandatory program.

As an alternative to a DEA-linked certification program, the industry working group also considered working with state medical boards to create mandatory CME programs for opioid prescribing, Nicholson said, “but we think a single entity provides the best chance of success, even if it requires legislative action.”

While prescriber education tied to DEA registration has garnered much discussion, there remain a variety of potential alternative approaches to reduce opioid-related unintentional deaths and injuries.

The Federation of State Medical Boards does not yet have a position on the mandatory DEA-linked prescriber program proposed by the industry working group, said Lisa Robin, senior vice president for advocacy and member services at the federation. However, the federation has created a model policy on opioid prescribing that 46 states have either adopted or adapted for use in their states (http://www.fsmb.org/pdf/2004_grpol_Controlled_Substances.pdf). The policy emphasizes that physicians should ensure patients have adequate pain control and also carefully monitor patients taking opioid analgesics for signs of misuse, and it provides criteria states can use to evaluate whether a physician is appropriately treating pain.

The federation has also created an opioid prescribing guide, which counts as CME, that has been distributed by 12 state boards to their members (http://www.fsmb.org/pain/). Additionally, various state medical boards are working to implement prescription monitoring programs and other initiatives to curb opioid abuse.

“We have advocated for the FDA to carefully consider the impact of any of these programs on the physician-patient relationship,” she said.

The American Academy of Pain Medicine has also submitted recommendations to the FDA suggesting, among other things, that the agency include all opioid medications in the safety plan. Scott M. Fishman, MD, chief of the division of pain medicine at the University of California-Davis and a former president of the academy, said that otherwise physicians may simply choose to prescribe short-acting opioids instead of long-acting or extended-release versions, even if a short-acting formulation is not the best option for the patient. That is exactly what happened, he said, when the state of California instituted a prescription monitoring program in which physicians were required to obtain triplicate prescription pads from law enforcement agencies to prescribe Schedule II (long-acting or sustained-release) opioids. He explained that many physicians substituted short-acting opioids rather than participate in the program. In turn, while abuse of Schedule II drugs decreased, abuse of the short-acting drug hydrocodone increased.

“We need to level the field for all these drugs, so all are equal when physicians are choosing one in the best interest of the patient,” said Fishman.

Jenkins said during the briefing that the FDA has chosen to focus on the long-acting products because the agency has detected a strong safety signal for these products, particularly methadone. However, he agreed that immediate-release products also pose safety concerns, and that the agency had not yet decided whether the scope of the safety plan should be extended to include them.

The American Academy of Pain Medicine has also proposed the creation of a national program or a linked state prescription monitoring program to allow physicians and pharmacists to access up-to-date information on their patients' prescriptions. Such a program could help prevent individuals from obtaining multiple opioid prescriptions from different clinicians.

While he believes that illegal use of prescription opioid drugs is largely driving the increase in opioid-associated deaths and injuries, Fishman, who also wrote the federation's opioid prescribing guide, said that a lack of physician education on proper use is contributing. He said such training should begin in medical school and extend to all licensed physicians, to ensure that patients have access to good pain management. One way to accomplish this might be to have state medical boards make such training a requirement for license renewal.

“Pain is the most common reason patients visit a doctor,” Fishman said. “It's an essential part of what we do. At some point, we must say if you are going to be a doctor, you must treat pain.”