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PROP versus PROMPT: FDA Speaks

After over a year of debate, petitions, and hearings, in September of 2013, the FDA announced class-wide safety labeling changes and new post-market study requirements for all extended-release and long-acting (ER/LA) opioid analgesics intended to treat pain. PPM asked the authors of PROP and PROMPT, as well as our Editorial Board, to weight in on the ruling.
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In July of 2012, Physicians for Responsible Opioid Prescribing (PROP) submitted a petition to the Food and Drug Administration (FDA) asking the agency to update labeling of opioid analgesics.1 According to a copy of the letter submitted to the FDA, the group stated that: “an increasing body of medical literature suggests that long-term use of opioids may be neither safe nor effective for many patients, especially when prescribed in high doses.” The group wanted the FDA to “exercise its regulatory responsibility over opioid manufacturers by prohibiting the marketing of opioids for conditions in which their use has not been proven safe and effective.”

The petitioners suggested specific action should be taken by the agency:

• Strike the term “moderate” from the indication for non-cancer pain

• Add a maximum daily dose, equivalent to 100 mg of morphine for non-cancer pain

• Add a maximum duration of 90 days for continuous (daily) use for non-cancer pain

In response to the PROP petition, a multidisciplinary group of clinicians involved in pain management formed Professionals for Rational Opioid Monitoring and Pharmacotherapy (PROMPT).2 According to the group’s Web site, the motivation for forming PROMPT was to address some of the concerns raised by PROP—the safe use of chronic opioids— “by mitigating these risks with appropriate proactive and ongoing validated interventions intended for the benefit of the patient care and public safety,” noted Jeffrey Fudin, BS, PharmD, and one of the founders of PROMPT.

FDA Ruling

After over a year of debate, petitions, and hearings, in September of 2013, the FDA announced class-wide safety labeling changes and new post-market study requirements for all extended-release and long-acting (ER/LA) opioid analgesics intended to treat pain.3 The actions of the FDA “demonstrates its resolve to reduce the serious risks of LA/ER opioids while still seeking to preserve appropriate access for those patients who rely on these medications to manage their pain,” noted FDA Commissioner Margaret A. Hamburg, MD. Given the serious risks of using ER/LA opioids, the class-wide labeling changes, when final, will include important new language to help physicians tailor their prescribing decisions based on a patient’s individual needs, noted the agency in a press release.

Some aspects of the FDA ruling pleased members on both side of the debate. The updated indication states that ER/LA opioids are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

The updated FDA indication further clarifies that, because of the risks of addiction, abuse, and misuse, even at recommended doses, and because of the greater risks of overdose and death, these drugs should be reserved for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain; ER/LA opioid analgesicsare not indicated for as-needed pain relief.

In addition, the FDA recognized that more information is needed to assess the serious risks associated with long-term use of ER/LA opioids. Therefore, the agency is requiring the drug companies that make these products to “conduct further studies and clinical trials. The goals of these postmarket requirements are to further assess the known serious risks of misuse, abuse, increased sensitivity to pain (hyperalgesia), addiction, overdose, and death.”

The FDA is also requiring a new boxed warning on ER/LA opioid analgesics to caution that chronic maternal use of these products during pregnancy can result in neonatal opioid withdrawal syndrome (NOWS), which may be life-threatening and require management according to protocols developed by neonatology experts. NOWS can occur in a newborn exposed to opioid drugs while in the mother’s womb. Symptoms may include poor feeding, rapid breathing, trembling, and excessive or high-pitched crying.

 In response to the citizen petitions submitted by PROP and PROMPT, Douglas Throckmorton, MD, deputy director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, noted that “the FDA remains committed to improving the safety of opioids and to continuing to engage in efforts to evaluate and mitigate the risks associated with opioid use. The safety labeling changes reflect the FDA’s current understanding of the risks and benefits of these products. The FDA will evaluate the results of the postmarket studies, continue to monitor relevant safety data, and take further safety action, as warranted,” he added.

PROP Response

Andrew Kolodny, MD, President of PROP, told Practical Pain Management that he was “disappointed that the FDA left the door wide open for drug companies to continue to promote opioids for conditions where the risks of use are likely to outweigh benefits.” For example, he noted that “the bulk of patients receiving opioids long-term for chronic pain suffer from low back pain, fibromyalgia, and chronic headache. Leading experts agree that opioids are a lousy treatment for these problems, and the risks of using opioids are likely to outweigh benefits.” Federal law, he added, is supposed to prohibit drug companies from promoting products for conditions where the risks are likely to outweigh benefits. “What PROP wanted was a narrower indication and more specific instructions on labels, such that use for these conditions [low back pain, fibromyalgia, chronic headache] would have been off-label—that is, allowed to be used by prescribers, but not allowed to be promoted by drug companies. That is what we were aiming for.”

On the other hand, Dr. Kolodny was pleased that the FDA agreed with their main argument—that evidence is lacking to support long-term and high-dose use of opioids, However, he noted that  “Since [the FDA] agreed with us that long-term use may be neither safe nor effective, they should have made chronic opioid therapy off-label now instead of asking drug companies to perform long-term trials and report back. What happens if the research proves that far more patients are harmed by chronic opioid therapy than helped? While the FDA waits for the drug companies to conduct trials, 100,000s of people may be started on a therapy that can be harmful and difficult to get off of.”

Last updated on: October 28, 2014
First published on: September 1, 2013