The FDA announced on July 31, 2025, that it is requiring comprehensive changes to the safety labeling of all opioid pain medications to emphasize and explain the serious risks associated with long-term use. This regulatory action follows the agency's review of data showing significant risks of misuse, addiction, and both fatal and non-fatal overdoses among long-term users.
The decision stems from findings in two large FDA-required observational studies, postmarketing requirements (PMR) 3033-1 and 3033-2, which provided new data demonstrating how long-term opioid use can lead to serious side effects. Combined with public comments, medical research, and what the agency identified as a lack of adequate studies on the long-term effectiveness of opioids, these findings prompted the FDA to mandate safety labeling changes to enable more informed treatment decisions by healthcare professionals and patients.
Comprehensive Label Requirements
The new labeling requirements include multiple critical safety updates. Manufacturers must provide clearer risk information, including summaries of study results showing estimated risks for addiction, misuse, and overdose during long-term use. The labels will feature stronger warnings that higher doses come with greater risks that persist over time.
The FDA is also requiring the removal of language that may be misinterpreted to support using opioid pain drugs indefinitely. New guidance will reinforce that long-acting or extended-release opioids should only be considered when other treatments, including shorter-acting opioids, are inadequate.
Additional safety measures include reminders that opioids should not be stopped suddenly in patients who may be physically dependent to avoid serious harm, along with information on drugs that can reverse an opioid overdose. The labels will feature enhanced warnings about combining opioids with other drugs that slow down the nervous system.
New Medical Information
The updated labels will include information about a serious brain condition that may occur after an overdose, known as toxic leukoencephalopathy, as well as updates about opioid-related impacts on the esophagus. Treatment guides will be revamped to reinforce that long-term usage should be a last resort treatment option.
Implementation Timeline and Future Studies
Relevant drug manufacturers have been given 30 days to submit their labeling updates to the FDA for review. The agency is also requiring an additional prospective, randomized, controlled clinical trial to examine the benefits and risks of long-term opioid use, with the FDA stating it will closely monitor these trials to ensure timely and efficient completion.
Leadership Response
FDA Commissioner Marty Makary, M.D., M.P.H., emphasized the significance of this action, stating, "The death of almost one million Americans during the opioid epidemic has been one of the cardinal failures of the public health establishment. 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."
Health and Human Services Secretary Robert F. Kennedy, Jr. added, "I know firsthand how devastating addiction is—not just for individuals, but for entire families and communities. Today's FDA action is a long-overdue step toward restoring honesty, accountability, and transparency to a system that betrayed the American people."
Related Regulatory Action
In related opioid policy developments, the FDA recommended on July 29, 2025, that 7-hydroxymitragynine (7-OH) products be classified under the Controlled Substance Act. This concentrated byproduct of the kratom plant binds to opioid receptors and has potential for abuse. While no 7-OH drugs are currently FDA-approved, the agency noted that approximately 1.7 million Americans aged 12 and older have used kratom-based products to self-treat pain, coughing, diarrhea, anxiety, and depression. The Drug Enforcement Administration is reviewing the FDA's recommendation on 7-OH scheduling.
