FDA Mandates Major Changes to Opioid Labeling

The FDA on July 31, announced a mandate for sweeping change to the safety labeling of all opioid pain medications, citing mounting evidence of long-term risks including misuse, addiction, and both fatal and nonfatal overdose.

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The agency’s action follows a May advisory committee meeting where experts reviewed new postmarketing data and longstanding concerns about the lack of evidence supporting chronic opioid use. The new labels will more explicitly detail the risks of extended use and remove language that could be misread as endorsing opioids for indefinite treatment durations.

“The death of almost one million Americans during the opioid epidemic has been one of the cardinal failures of the public health establishment,” said FDA Commissioner Marty Makary, M.D., M.P.H. “This long-overdue labeling change is only part of what needs to be done — we also need to modernize our approval processes and post-market monitoring so that nothing like this ever happens again.”

The updated language draws on findings from two large observational studies—PMR 3033-1 and 3033-2—mandated by the FDA as a condition of earlier approvals. Those studies added to a growing body of literature showing that prolonged use of opioids can result in serious harm, especially in the absence of clear benefit over time. The FDA acknowledged that when OxyContin was approved in the 1990s, its labeling lacked sufficient data supporting long-term use in many patient populations. The agency now asserts that prescribing decisions must be informed by more recent evidence, and has called for additional clinical trials to evaluate long-term opioid therapy in a controlled setting.

“I know firsthand how devastating addiction is—not just for individuals, but for entire families and communities,” said HHS Secretary Robert F. Kennedy, Jr. “Today’s FDA action is a long-overdue step toward restoring honesty, accountability, and transparency to a system that betrayed the American people.”

The agency is requiring manufacturers to submit revised labeling within 30 days. In addition to the new warnings, the FDA will also be monitoring progress on a newly required randomized, controlled trial designed to provide further insight into the risks and benefits of long-term opioid use.

The American Medical Association gave its full endorsement to the new requirements in a statement from President Bobby Mukkamala, MD:

The FDA’s requirement on opioid labels appropriately focuses on physicians making individualized, informed decisions about opioid prescribing while supporting informed decision-making for patients. The AMA agrees that decisions whether to begin opioid therapy must be made on whether the benefits outweigh the known risks. We agree that—if opioid therapy is indicated—physicians should start low and go slow. We further agree with the FDA that rapid escalations and rapid discontinuation should not occur to avoid patient harm.

In a letter to Makary following the May 2025 advisory committee meeting, the FDA commended the shift in label emphasis, noting the step as a sequel the CDC action in 2022 to revise draconian and widely damaging changes to opioid prescribing policy established in 2016.

A good example of the need to reevaluate well-intentioned but misapplied guidance was why the U.S. Centers for Disease Control and Prevention (CDC) took action to understand the implications and unintended consequences of its 2016 CDC Clinical Practice Guideline for Prescribing Opioids and revised those guidelines in 2022. The CDC authors said that the 2022 CDC revision made multiple critical revisions and clarifications to emphasize that the guideline [in part] '[P]rovides recommendations but does not replace clinical judgment and individualized, patient-centered decision-making.'”

At the same time the AMA correspondence highlights the progress made across numerous metrics used to assess the nation's epidemic of opioid overdose and death, including a reduction in total opioid prescriptions and dosage strength and research into abuse-deterrent opioid formulations. The letter concludes with:

Rather than reconsider failed approaches to improve care with arbitrary prescribing thresholds, the AMA urges continued efforts to identify promising new treatments for pain as well as continuing education and training for all types of pain.

The proposed changes to opioid labeling include:

• Clearer risk information: A summary of study results showing the estimated risks of addiction, misuse, and overdose during long-term use.
• Dosing warnings: Stronger warnings that higher doses come with greater risks, and that those risks remain over time.
• Clarified use limits: Removing language which could be misinterpreted to support using opioid pain medications over indefinitely long duration.
• Treatment guidance: Labels will reinforce that long-acting or extended-release opioids should only be considered when other treatments, including shorter-acting opioids, are inadequate.
• Safe discontinuation: A reminder not to stop opioids suddenly in patients who may be physically dependent, as it can cause serious harm.
• Overdose reversal agents: Additional information on medicines that can reverse an opioid overdose.
• Drug interactions: Enhanced warning about combining opioids with other drugs that slow down the nervous system—now including gabapentinoids.
• More risks with overdose: New information about toxic leukoencephalopathy—a serious brain condition that may occur after an overdose.
• Digestive health: Updates about opioid-related problems with the esophagus.

More information is available in the FDA’s Drug Safety Communication.