FDA Requires New Opioid Labeling on Long-Term Use (2025)

Table of Contents

1. What the FDA Did
2. Terms Explained: Opioid Analgesics, IR and ER/LA, Labeling and Postmarketing Requirements
3. The Core Labeling Changes on Long-Term Use
4. Added Warnings: Overdose Reversal, Gabapentinoids, Brain and Esophagus
5. Where the Data Came From: Postmarketing Requirements 3033-1 and 3033-2
6. What the Two Studies Found
7. The Limits the FDA Attaches to the Findings
8. The May 2025 Advisory Committee Meeting
9. What the FDA Told Clinicians and Patients
10. What the Action Does Not Do
11. Dates and Status (as of 11 October 2026)
12. How It Fits Earlier FDA Opioid Actions
13. Primary Documents
14. Key Research Papers
15. Connections

1. What the FDA Did

The FDA announced the action on 31 July 2025 in two documents: a news release titled “FDA Requires Major Changes to Opioid Pain Medication Labeling to Emphasize Risks” and a Drug Safety Communication titled “FDA is requiring opioid pain medicine manufacturers to update prescribing information regarding long-term use.” The communication’s subtitle describes it as a “class-wide action” that “will further emphasize and characterize risks of long-term use to help patients, health care professionals make informed treatment decisions.”

The news release states that the FDA “is requiring safety labeling changes to all opioid pain medications to better emphasize and explain the risks associated with their long-term use.” According to the release, the FDA sent letters to the relevant applicants (the companies that hold approval for these medicines) outlining the required changes, and the companies had 30 days to submit their labeling updates to the FDA for review.

The release gives the reasons for the decision: the results of two FDA-required observational studies, public comments, the medical literature, and what it calls “the absence of adequate and well-controlled studies on long-term opioid effectiveness.” It also states that an extended-release oxycodone product was initially approved without study data supporting its long-term use to treat pain in many of the patient populations for which it has been prescribed.

The release quotes FDA Commissioner Marty Makary, M.D., M.P.H.: “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.” It also quotes the Secretary of Health and Human Services, Robert F. Kennedy, Jr., who called the action “a long-overdue step toward restoring honesty, accountability, and transparency to a system that betrayed the American people.”

In addition to the labeling changes, both documents state that the FDA has required a prospective, randomized, controlled clinical trial to examine the benefits and risks of long-term opioid use directly. The release says the agency “will be closely monitoring the progress of this clinical trial to ensure its timely completion.”

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2. Terms Explained: Opioid Analgesics, IR and ER/LA, Labeling and Postmarketing Requirements

• Opioid analgesic (opioid pain medicine). The Drug Safety Communication describes these as “a class of powerful pain medicines prescribed to treat pain that does not respond well to other treatments.” The examples it lists are codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, fentanyl, buprenorphine, methadone and tramadol.
• Immediate-release (IR) and extended-release/long-acting (ER/LA). The FDA describes the two main categories: IR products “are usually intended for use every four to six hours as needed for acute pain,” while ER/LA products “are intended to be taken only once or twice a day for severe and persistent pain that cannot be adequately treated with alternative options.”
• Labeling (prescribing information). The official document approved by the FDA for each medicine, read mainly by prescribers. Its “Indications and Usage” section states what the medicine is approved to treat. The patient-facing Medication Guide is handed out with the filled prescription.
• Safety labeling change. A change to the labeling that the FDA requires once it decides new safety information belongs there. Here the FDA notified every holder of an approval for these medicines by letter.
• Postmarketing requirement (PMR). A study the FDA requires a company to carry out after a medicine is already on the market. The FDA states it used its authority under Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act to require the holders of ER/LA opioid approvals to conduct the two studies behind this action.
• Drug Safety Communication. The FDA’s public notice format for new safety information about a medicine, addressed to both health care professionals and patients.
• Gabapentinoids. A group of medicines that includes gabapentin and pregabalin, used for nerve pain and seizures. The site’s Non-Opioid Medications for Chronic Pain page describes them.

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3. The Core Labeling Changes on Long-Term Use

The Drug Safety Communication lists the changes the FDA notified approval holders were needed. Three concern long-term use directly:

1. Removing “extended treatment period.” The phrase is to come out of the Indications and Usage section, which the FDA says is “to avoid misinterpretation that there are data to support safety and efficacy of opioid analgesics over an indefinitely long duration.”
2. Dose and duration. The labeling is to “further emphasize that higher doses are associated with increased risk of serious harm, and that the risks of serious harms persist over the course of therapy.”
3. The study results. The labeling is to give “a brief description of the results of studies conducted to fulfill postmarketing requirements 3033-1 and 3033-2, including new quantitative estimates of the risks of addiction, abuse, misuse, and fatal and non-fatal overdose in patients taking opioid analgesics long-term.”

Two further changes clarify where ER/LA products fit and how treatment ends. The FDA is requiring updates “to further clarify that extended-release/long-acting opioid pain medicines should only be used when alternative therapies, including immediate-release opioid pain medicines, are inadequate to manage severe and persistent pain,” and “to emphasize the importance of avoiding rapid dose reduction or abrupt discontinuation in patients who may be physically dependent on opioid pain medicines.” That wording is the FDA’s required label language, reported here as such.

The news release summarizes the same changes under the headings Clearer Risk Information, Dosing Warnings, Clarified Use Limits, Treatment Guidance and Safe Discontinuation. The FDA also published a table of the key opioid label updates as a separate PDF alongside the communication.

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4. Added Warnings: Overdose Reversal, Gabapentinoids, Brain and Esophagus

The communication lists four additional labeling updates that apply to the class:

• Overdose reversal agents. Information on the availability of medicines that reverse an opioid overdose. The communication names naloxone and nalmefene, notes that the FDA approved the first over-the-counter naloxone nasal spray in March 2023 and the first nalmefene hydrochloride auto-injector (a prescription product for adults and children 12 and older) in August 2024, and states that naloxone is available over the counter and by prescription while nalmefene hydrochloride is prescription only.
• Central nervous system depressants, now including gabapentinoids. The drug-interaction section on medicines that slow the nervous system is revised to include gabapentinoids. Elsewhere the communication describes “the added risks of using opioid pain medicines with benzodiazepines and other central nervous system depressants, including gabapentinoids,” and lists alcohol among the substances that raise overdose risk when combined with opioids.
• Toxic leukoencephalopathy. Information about this condition in the opioid overdose setting. The FDA defines it as “a neurological disorder due to a variety of causes, including exposure to toxic substances”; the news release calls it “a serious brain condition that may occur after an overdose.”
• Opioid-induced esophageal dysfunction. The warnings about gastrointestinal effects are modified to include problems with the esophagus (the swallowing tube) caused by opioids.

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5. Where the Data Came From: Postmarketing Requirements 3033-1 and 3033-2

According to the communication’s Background and Data Summary, the FDA required the holders of ER/LA opioid approvals to conduct epidemiologic studies to quantify the serious risks of misuse, abuse, addiction and fatal and non-fatal overdose in long-term users, and to assess risk factors. The studies were completed by a consortium of all the ER/LA opioid application holders, under protocols and analysis plans that the FDA reviewed and that were discussed at a public scientific workshop. Both drew on patients in health insurance plans and health systems across the United States.

PMR 3033-1 was a prospective (forward-looking) observational cohort study of adults starting long-term use of Schedule II opioid pain medicines. Patients were recruited and followed from 2017 through 2021. It had two cohorts: an ER/LA cohort (patients who filled several ER/LA prescriptions within 90 days) and a long-term opioid therapy cohort (patients with Schedule II opioid prescriptions covering at least 70 of 90 days). People with a terminal illness, a recent diagnosis of opioid use disorder, treatment with methadone or buprenorphine for opioid use disorder, or hospice care were excluded. The FDA reports that 978 and 1,244 patients were included in one or more analyses in the two cohorts. Misuse and abuse were measured with a validated self-report questionnaire; addiction was measured with a validated semi-structured psychiatric interview.

PMR 3033-2 was a retrospective (looking back at records) observational cohort study of 220,249 adults with new long-term use of Schedule II opioid pain medicines between 2006 and 2016, drawn from two commercial insurance programs, one managed care program and one Medicaid program. New long-term use meant prescriptions covering at least 70 days’ supply over three months, with none in the six months before. The outcome was the first opioid-involved overdose or opioid overdose-related death, found through a validated medical-code algorithm linked to the National Death Index. The communication notes that hydrocodone combination products, moved from Schedule III to Schedule II in October 2014, were treated as Schedule II throughout.

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6. What the Two Studies Found

The FDA’s communication reports these results (rounded as the FDA rounds them):

• Misuse. Over 12 months, about 22% of included patients across the two cohorts of PMR 3033-1 newly met criteria for prescription opioid misuse (22.8% in the ER/LA cohort, 21.6% in the long-term therapy cohort). The FDA defines misuse as intentional use for a therapeutic purpose but outside the label or in a way other than prescribed.
• Abuse. Over 12 months, about 9% newly met criteria for prescription opioid abuse (9.4% and 8.6%). The FDA defines abuse as intentional use for a nontherapeutic purpose, such as achieving a positive psychological or physical effect.
• Addiction (moderate-to-severe opioid use disorder). Over 12 months, about 3–6% newly met standard DSM-5 criteria and about 1–2% met a modified, pain-adjusted version of the criteria that counted most symptoms only when the patient gave a non-pain reason for opioid use. The FDA summarizes the range as “approximately 1-6%.”
• Overdose. In PMR 3033-2 the five-year cumulative incidence of a first opioid-involved overdose or overdose death ranged from about 1.5% to about 4% across the four data sites, and rose steadily throughout follow-up. Over the whole study period (5 to 11 years, depending on the site), about 17% of first overdoses were fatal.
• Risk factors. One of the strongest and most consistent risk factors for misuse, abuse, addiction and overdose was a personal history of a substance use disorder. A higher opioid dose in the three months before entering the study was a strong and consistent risk factor for overdose.

The FDA adds that a notable share of patients starting long-term therapy already had a substance use disorder history: in PMR 3033-1, 6.5% to 8% had a non-opioid, non-nicotine substance use disorder in the past year, and 29% to 34.1% had one before the past year; in PMR 3033-2, about 4–6% each had a diagnosis of opioid use disorder, alcohol use disorder or another substance use disorder.

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7. The Limits the FDA Attaches to the Findings

The communication sets out several cautions about how far the numbers reach:

• Both studies were restricted, by design, to the relatively small share of patients who go on to use opioids long term, so they “do not inform quantitative questions of risk related to shorter-term use.” The FDA says the estimates “may not be generalizable to all patients receiving opioid analgesics.”
• In PMR 3033-1, factors such as possible volunteer bias and the predominance of managed care and integrated health systems may have limited how generalizable and interpretable the findings are.
• In PMR 3033-2, the overdoses counted may not have involved the prescribed opioid; they could have happened after a patient stopped the prescription and could have involved illicit opioids such as heroin or fentanyl. Only the first overdose was counted, so later events, including fatal ones, were not. Whether an overdose was a suicide attempt or accidental could not be adequately confirmed. Overdoses reversed by a bystander without a medical claim or death were not captured.
• Loss to follow-up was substantial (about 80%), and excluding people with a recent overdose likely selected a lower-risk group; the FDA says both may have biased the estimates.
• Neither study was designed to assess whether changing the dose or stopping opioids was associated with harm.

The FDA’s conclusion is that “these new data may help inform the benefit-risk assessment in patients for whom long-term use of opioid analgesics is being considered.” The separate randomized trial it has required is meant to examine the risks relative to the efficacy of long-term opioid use, a question these observational studies were not built to answer.

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8. The May 2025 Advisory Committee Meeting

An FDA advisory committee is a panel of outside experts that gives the agency non-binding advice in a public meeting. Before deciding, the FDA convened a joint meeting of two of them, the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee, to discuss the findings of PMRs 3033-1 and 3033-2.

The meeting was first announced in the Federal Register on 9 December 2024 (89 FR 97625) for 5 February 2025. An amendment published on 21 April 2025 (90 FR 16692) moved it to 5 May 2025, from 8 a.m. to 5 p.m. Eastern Time. Both notices name public docket FDA-2024-N-5331; a Federal Register docket is the public file where anyone may submit written comments. The amended notice states that the docket closed on 4 May 2025 and that comments received by 21 April 2025 would be provided to the committees.

The Drug Safety Communication states that after “reviewing the study findings and the medical literature, as well as considering the committees’ and public input,” the FDA determined that the new information belonged in drug labeling. The FDA documents used for this page do not report how the committee members voted, so no vote is given here.

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9. What the FDA Told Clinicians and Patients

The Drug Safety Communication includes advice addressed to health care professionals and to patients. It is the FDA’s advice, reported here as the agency states it.

To health care professionals, the FDA advises, among other points:

• to use a multimodal approach to pain management and to consider non-drug, non-interventional treatments that address the root cause of the pain, where possible;
• where an opioid is needed and alternatives are insufficient, to prescribe the lowest effective dose of an immediate-release opioid for the shortest duration needed, and to consider an IR opioid as an as-needed, first-line treatment; the FDA notes that many acute pain conditions, such as pain after surgery or musculoskeletal injuries, require no more than a few days;
• to reserve ER/LA opioids for severe and persistent pain that cannot be adequately treated with alternatives, including IR opioids, and to regularly re-evaluate the benefit-risk balance and assess for addiction, abuse or misuse;
• to discuss overdose reversal agents with all patients prescribed opioids, and to inform patients of the added risk of combining opioids with benzodiazepines and other nervous-system depressants, including gabapentinoids;
• to remind patients that opioid use can paradoxically increase pain (opioid-induced hyperalgesia);
• to avoid rapidly reducing or abruptly stopping opioids in patients who may be physically dependent, “because such changes have resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.”

To patients and caregivers, the FDA’s advice includes taking the medicine exactly as prescribed; talking with a health care professional if pain increases, sensitivity to pain grows, or new pain appears from things that are not usually painful; storing the medicines securely and disposing of unused ones through take-back or mail-back programs; not reducing or stopping the medicine rapidly without consulting a health care professional; and asking about naloxone and nalmefene. The FDA lists the signs of an overdose as slowed, shallow or difficult breathing, severe sleepiness, or not being able to respond or wake up, and advises seeking emergency medical help or calling 911 if they occur.

The FDA also states that, because people respond differently to medicines, “we cannot determine how likely it is that someone will experience these side effects.” Decisions about any individual’s pain treatment belong with the clinician who knows that person’s history. The FDA invites patients and professionals to report side effects to its MedWatch program.

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10. What the Action Does Not Do

• It does not withdraw any opioid medicine from the market or remove any product’s approval.
• It does not set a legal limit on dose, duration or prescribing; it changes what the labeling says. The FDA’s statements to clinicians are advice, not a rule.
• It does not replace the 2023 class-wide opioid labeling updates; it builds on them (see section 12).
• It does not establish whether long-term opioid therapy works. The FDA itself points to “the absence of adequate and well-controlled studies on long-term opioid effectiveness” and has required a separate randomized trial for that question.
• It does not give risk estimates for short-term use: the FDA states that the two studies do not inform questions of risk related to shorter-term use.
• It was not issued as a proposed rule and had no comment period of its own; a check of the Federal Register found no document announcing the labeling decision. The public docket belonged to the earlier advisory committee meeting.

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11. Dates and Status (as of 11 October 2026)

• 9 December 2024 — Federal Register notice of the joint advisory committee meeting on PMRs 3033-1 and 3033-2, docket FDA-2024-N-5331 opened.
• 21 April 2025 — amended notice moves the meeting to 5 May 2025.
• 5 May 2025 — joint meeting of the Drug Safety and Risk Management and Anesthetic and Analgesic Drug Products advisory committees.
• 31 July 2025 — FDA news release and Drug Safety Communication announce the required labeling changes; letters sent to approval holders, who had 30 days to submit their labeling updates.
• 3 April 2026 — the “content current as of” date shown on the FDA’s Drug Safety Communication web page when it was fetched for this page.

Status as of 11 October 2026: the labeling changes are an FDA requirement, announced as a final decision rather than a proposal. The FDA documents used for this page do not report when the revised labeling for each product was approved and put into use, so this page describes the changes as required, not as completed. No FDA document reporting the results of the required randomized trial was located.

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12. How It Fits Earlier FDA Opioid Actions

The 2025 action follows a round of class-wide opioid labeling updates that the FDA first described in an April 2023 Drug Safety Communication and gave final approval to on 15 December 2023. According to the FDA’s December 2023 statement, those updates added language stating that overdose risk increases as dosage increases for all opioid pain medicines; that IR opioids are not meant for an extended period unless pain remains severe enough and alternatives continue to be inadequate; that many acute pain conditions treated outside the hospital require no more than a few days of an opioid; and that ER/LA opioids are recommended to be reserved for severe and persistent pain “that requires an extended treatment period with a daily opioid pain medicine” and for which alternatives are inadequate. The 2023 updates also added a warning about opioid-induced hyperalgesia.

The 2025 changes revisit that last point: the phrase “extended treatment period” is now to be removed from the Indications and Usage section, for the reason the FDA gives in section 3. The December 2023 statement placed those updates within the FDA Overdose Prevention Framework, whose stated priorities include “eliminating unnecessary initial prescription drug exposure and inappropriate prolonged prescribing.”

Among the other FDA actions of 2025 reported on this site, the agency’s steps against concentrated 7-hydroxymitragynine (7-OH) products, an opioid-acting compound related to kratom, are described on the 7-OH kratom page, with the 2026 follow-up on 7-OH Kratom Products: The 2026 Scheduling Steps. The full list is on the FDA Actions of 2025 hub.

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13. Primary Documents

1. U.S. Food and Drug Administration (2025). FDA Requires Major Changes to Opioid Pain Medication Labeling to Emphasize Risks. FDA News Release, 31 July 2025 — fda.gov news release
2. U.S. Food and Drug Administration (2025). FDA is requiring opioid pain medicine manufacturers to update prescribing information regarding long-term use. FDA Drug Safety Communication, 31 July 2025 (web page content current as of 3 April 2026) — fda.gov Drug Safety Communication (PDF, 570 KB)
3. U.S. Food and Drug Administration (2025). Key Opioid Label Updates (table of changes, July 2025) — fda.gov PDF, 379 KB
4. Food and Drug Administration, HHS (2024). Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments—Extended-Release/Long-Acting Opioid Analgesic Postmarketing Requirement. Federal Register 89:97625–97627, 9 December 2024. Docket No. FDA-2024-N-5331 — FR Doc. 2024-28811
5. Food and Drug Administration, HHS (2025). Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee; Amendment of Notice—Extended-Release/Long-Acting Opioid Analgesic Postmarketing Requirement. Federal Register 90:16692, 21 April 2025. Docket No. FDA-2024-N-5331 — FR Doc. 2025-06787 (official PDF, govinfo.gov)
6. U.S. Food and Drug Administration (2023). FDA approves safety labeling changes for opioid pain medicines. FDA Drug Alerts and Statements, 15 December 2023 — fda.gov statement

No Federal Register document announcing the labeling decision itself was found; the docket listed above belongs to the advisory committee meeting.

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Key Research Papers

1. Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, Dana T, Bougatsos C, Deyo RA (2015). The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Annals of Internal Medicine 162(4):276-286 — PubMed PMID: 25581257
2. Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, Kroenke K, Bair MJ, Noorbaloochi S (2018). Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. JAMA 319(9):872-882 — PubMed PMID: 29509867
3. Bohnert AS, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA, Blow FC (2011). Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 305(13):1315-1321 — PubMed PMID: 21467284
4. Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W (2017). Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Medicine 14(10):e1002396 — PubMed PMID: 28972983
5. Oliva EM, Bowe T, Manhapra A, Kertesz S, Hah JM, Henderson P, Robinson A, Paik M, Sandbrink F, Gordon AJ, Trafton JA (2020). Associations between stopping prescriptions for opioids, length of opioid treatment, and overdose or suicide deaths in US veterans: observational evaluation. BMJ 368:m283 — PubMed PMID: 32131996
6. Ratuapli SK, Crowell MD, DiBaise JK, Vela MF, Ramirez FC, Burdick GE, Lacy BE, Murray JA (2015). Opioid-Induced Esophageal Dysfunction (OIED) in Patients on Chronic Opioids. American Journal of Gastroenterology 110(7):979-984 — PubMed PMID: 26032150
7. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R (2022). CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022. MMWR Recommendations and Reports 71(3):1-95 — PubMed PMID: 36327391

These papers cover the topics the labeling changes address: the evidence base for long-term opioid therapy (a systematic review and a randomized trial), dose and overdose risk, the combination of gabapentin and opioids, stopping opioid prescriptions, opioid-induced esophageal dysfunction, and the 2022 federal prescribing guideline. None of them is cited in the FDA documents listed above, which do not give a reference list.

PubMed Topic Searches

1. PubMed: long-term opioid therapy, addiction and overdose
2. PubMed: gabapentinoids, opioids and respiratory depression
3. PubMed: opioid toxic leukoencephalopathy
4. PubMed: opioid tapering and discontinuation outcomes

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Connections

• FDA Actions of 2025
• FDA and Regulation
• Opioids for Chronic Non-Cancer Pain
• Non-Opioid Medications for Chronic Pain
• Chronic Pain
• Opioid Overdose
• Addiction and Substance Use Disorders
• Concentrated 7-OH Kratom Products (2025)
• 7-OH Kratom Scheduling Steps (2026)
• ADHD Stimulant Label Under Age 6 (2025)
• Acetaminophen Pregnancy Label Change (2025)
• Hormone Therapy Labeling Change Request (2025)
• Misleading Drug Advertising Crackdown (2025)

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