FDA Requires New Safety Labeling for All Opioid Pain Medicines (2023)

Table of Contents

1. What the FDA Did
2. The Data the FDA Gave for Acting
3. Immediate-Release, Long-Acting and the Label Itself
4. New Wording on Use, Dose and Duration
5. The Boxed Warning, Reordered
6. The New Warning on Opioid-Induced Hyperalgesia
7. Changes to the Patient Medication Guides
8. What the FDA Told Clinicians and Patients
9. What the Action Does Not Do
10. Dates and Legal Status as of 18 October 2026
11. How the Action Fits Other FDA Opioid Actions
12. Primary Documents
13. Key Research Papers
14. Connections
15. Featured Videos

1. What the FDA Did

The Drug Safety Communication of 13 April 2023 is titled “FDA updates prescribing information for all opioid pain medicines to provide additional guidance for safe use,” with the subtitle “Includes updates to help reduce unnecessary prescribing.” It opens by saying that, “as part of its ongoing efforts to address the nation’s opioid crisis,” the FDA is “making several updates to the prescribing information of opioid pain medicines to provide additional guidance on the use of these powerful medicines.”

The communication lists what the agency is requiring for both immediate-release (IR) and extended-release/long-acting (ER/LA) opioid pain medicines:

• a statement, for all opioid pain medicines, that the risk of overdose increases as the dose increases;
• for IR opioids, wording that they are not to be used for an extended period unless the pain remains severe enough to require them and alternative treatments continue to be inadequate, and that many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine;
• for ER/LA opioids, an updated approved use recommending that they be reserved for severe and persistent pain that requires an extended treatment period with a daily opioid and for which alternatives are inadequate;
• a new warning about opioid-induced hyperalgesia (OIH) for both IR and ER/LA products, including how to tell its symptoms apart from opioid tolerance and withdrawal;
• an updated and reordered Boxed Warning, with other changes to the Indications and Usage, Dosage and Administration, and Warnings and Precautions sections; and
• updates to the existing patient Medication Guides.

The FDA’s December 2023 statement explains how the requirement reached the companies: in April 2023 the agency “notified application holders of New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) of required safety labeling updates.” These are the two kinds of drug application named in the statement; because the notice went to holders of both, the required changes reach every opioid pain medicine approved under either kind.

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2. The Data the FDA Gave for Acting

The communication’s “Background and Data Summary” sets out the numbers behind the action, each drawn from the federal and published sources listed in its references:

• Overdose deaths overall. Opioid-involved overdose deaths “have risen steadily over the past 15 years,” with a dramatic increase from 47,600 deaths in 2017 to 80,411 in 2021. The FDA notes that most opioid-involved deaths are due to illicit fentanyl and fentanyl analogs.
• Prescriptions fell, deaths did not. Opioid pain medicine dispensing fell from 81.3 prescriptions per 100 persons in 2012 to 43.3 per 100 in 2020, yet prescription-opioid-involved overdose deaths “remained relatively steady over time, with 16,706 deaths in 2021.” The FDA adds that these statistics “likely underestimate” the role of prescription opioids in overall opioid-related deaths.
• From prescription to illicit use. In one interview study (2019–2021) of 148 people in three states who reported using heroin, illicit fentanyl or prescription opioids nonmedically, 90 percent said their first exposure involved prescription opioid pain medicines, and nearly half of those (48 percent) had obtained them through a prescription. Some participants said policies that limited access to prescription opioids in inappropriate ways, such as rapid discontinuation, may have influenced their move to illicit opioids.
• Opioid use disorder. Among Americans aged 12 and older, 5.6 million (2 percent) reported having an opioid use disorder in the past year in 2021.
• Leftover tablets after surgery. A systematic review of studies published through 2019 found that, among studies reporting excess tablets, 25 to 98 percent of the tablets prescribed after surgery went unused, with most studies reporting 50 to 70 percent. The FDA says unused tablets that are not properly disposed of provide opportunities for nonmedical use, accidental exposure and overdose, including by children and teenagers.
• Dose and risk. The FDA writes that data “strongly suggest that the risk of overdose increases as the prescribed dosage of opioid pain medicines increases,” and that this risk can occur at any point during treatment.
• Other options. For many acute and chronic pain conditions, the communication says, non-opioid treatments, both drug and non-drug, have been found effective, and for a number of conditions non-opioid medicines “may be just as effective as opioid pain medicines.”

The communication also lists harms beyond deaths: non-fatal overdoses can bring complications such as opioid-induced respiratory depression and brain injury, and the crisis affects children and families through mental health problems, drug use, accidental opioid poisoning and the loss of a parent to overdose.

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3. Immediate-Release, Long-Acting and the Label Itself

Three terms explain what kind of action this was:

• Opioid pain medicines. The communication describes them as “a class of powerful pain medicines prescribed to treat pain that does not respond well to other treatments or non-opioid pain medicines,” which act on nerve cells in the brain and body to block pain signals. Its examples are codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, fentanyl, buprenorphine and tramadol. They come as tablets, capsules, lozenges, tablets dissolved under the tongue, skin patches, nasal sprays and injections.
• IR and ER/LA. According to the FDA, immediate-release products are usually intended for use every 4 to 6 hours as needed for acute pain. Extended-release/long-acting products are intended to be taken only once or twice a day for severe and persistent pain that requires an extended treatment period and for which alternatives are inadequate.
• Prescribing information and Medication Guide. The prescribing information (the “label”) is, in the communication’s words, the “essential information that prescribers need to prescribe opioid pain medicines appropriately”; the sections the FDA changed include the Boxed Warning, Indications and Usage, Dosage and Administration, and Warnings and Precautions. The communication calls the Boxed Warning “FDA’s most prominent warning.” The Medication Guide comes with a filled prescription and, the FDA says, explains “the important things they need to know about the medicine,” including side effects and how to take, store and dispose of it.

The FDA’s side-by-side table, “Key Opioid Label Updates,” says the changes apply to opioid pain medicines intended for use in the outpatient setting, “although many also apply to opioid analgesics used in the inpatient setting.” It calls its examples representative rather than exhaustive and notes other minor updates. The table also gives the FDA’s definitions: misuse is the intentional use, for therapeutic purposes, of a drug other than as prescribed or by someone for whom it was not prescribed; abuse is the intentional, nontherapeutic use of a drug for its psychological or physical effects. The FDA adds that the term abuse “is not intended to imply moral judgment.”

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4. New Wording on Use, Dose and Duration

The “Key Opioid Label Updates” table shows the former and new wording. The main changes, quoted from the new column:

• Long-acting opioids: what they are approved for. The former indication read “pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatments are inadequate.” The new indication reads “severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.” ER/LA products remain “not indicated as an as-needed (prn) analgesic.”
• Risk at any dose. In the Limitations of Use for both IR and ER/LA products, the former phrase that addiction, abuse and misuse can occur “even at recommended doses” becomes “which can occur at any dosage or duration.”
• Immediate-release opioids: duration. A new sentence reads that the product “should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.”
• Dose and overdose. New Dosage and Administration text for IR and ER/LA products: “Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses … for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.”
• A few days for many acute conditions. New IR text: “Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic.” It adds that clinical guidelines on opioid prescribing for some acute pain conditions are available, and that the dose and duration needed vary with the cause of pain and the individual patient.
• Who prescribes. IR labels gain the sentence that the product “should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks”; the ER/LA wording is updated in the same direction.
• Breathing risk at any time. The former instruction to monitor closely for respiratory depression “especially within the first 24-72 hours” is replaced by: “Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases.”
• Starting dose. For an IR opioid used as a first opioid, the starting-dose text adds “at the lowest dose necessary to achieve adequate analgesia,” with the dose then titrated to the individual patient’s response.
• Switching to a long-acting opioid. The former text said to discontinue all other around-the-clock opioids when an ER/LA product is started; the new text says to discontinue all opioid analgesics “other than those used on an as needed basis for breakthrough pain when appropriate.”

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5. The Boxed Warning, Reordered

The communication states that the Boxed Warning for all IR and ER/LA opioid pain medicines “will be updated and reordered to elevate the importance of warnings concerning life-threatening respiratory depression, and risks associated with using opioid pain medicines in conjunction with benzodiazepines or other medicines that depress the central nervous system (CNS).”

The FDA’s table gives the order before and after, with shortened wording:

• Former order: Addiction, Abuse, and Misuse; the Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS); Life-Threatening Respiratory Depression; Accidental Ingestion; Neonatal Opioid Withdrawal Syndrome; Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants.
• New order: Addiction, Abuse, and Misuse; Life-Threatening Respiratory Depression; Accidental Ingestion (unchanged); Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants; Neonatal Opioid Withdrawal Syndrome (NOWS); and, last and shortened, the REMS.

The former box explained that the FDA had required the REMS “to ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse,” and that under it drug companies must make REMS-compliant education programs available to healthcare providers. In the new box the respiratory-depression item states that serious, life-threatening or fatal respiratory depression may occur “especially during initiation or following a dose increase,” and the combination item states that using opioids with benzodiazepines or other CNS depressants, including alcohol, “may result in profound sedation, respiratory depression, coma, and death.” The accidental-ingestion item keeps its wording that even one dose, “especially by children, can result in a fatal overdose.” The neonatal item concerns withdrawal symptoms in a newborn after opioid use in pregnancy; its new wording speaks of use “for an extended period of time in a pregnant woman.”

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6. The New Warning on Opioid-Induced Hyperalgesia

The FDA describes opioid-induced hyperalgesia as the situation in which “an opioid that is prescribed and taken for pain relief causes an increase in pain (called hyperalgesia) or an increased sensitivity to pain (called allodynia).” Allodynia means pain from things that are not normally painful; the communication’s example is combing one’s hair. According to the FDA, OIH can occur at any dosage but may occur more often with higher doses and longer-term use. It “can be difficult to recognize and may result in increased opioid dosages that could worsen symptoms and increase the risk of respiratory depression.”

The cases. The FDA identified 46 cases describing hyperalgesia and allodynia in people using opioid pain medicines for pain: 8 with short-term use and 38 with longer-term use. The cases came from the FDA Adverse Event Reporting System and the medical literature, “so there may be cases about which we are unaware.” The medicines involved most often were morphine, hydromorphone and fentanyl or fentanyl analogs. Cancer was the most reported underlying condition being treated. Other possible causes of the increased pain, such as worsening disease, were excluded, and patients reported improvement in pain after stopping the opioid. The FDA says the mechanism “is not fully understood,” though multiple biochemical pathways have been suggested.

The new label section. The Warnings and Precautions section gains a new subsection, “Opioid-Induced Hyperalgesia and Allodynia.” Its text, as given in the FDA table, says OIH occurs when an opioid “paradoxically causes an increase in pain, or an increase in sensitivity to pain,” and distinguishes it from tolerance, “the need for increasing doses of opioids to maintain a defined effect.” The symptoms it lists are:

• increased levels of pain when the opioid dose is increased;
• decreased levels of pain when the opioid dose is decreased;
• pain from ordinarily non-painful stimuli (allodynia).

The label says these symptoms may suggest OIH “only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior,” and that “medical literature suggests a strong biologic plausibility” linking opioid analgesics with OIH and allodynia. For a patient suspected of having OIH, it describes two options for prescribers to consider: carefully decreasing the dose of the current opioid, or opioid rotation, meaning switching to a different opioid.

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7. Changes to the Patient Medication Guides

The FDA table shows three representative changes to the leaflets patients receive:

• Long-acting products. The description of what the medicine is for now matches the new indication (“severe and persistent pain that requires an extended treatment period with a daily opioid medicine”), and “Not for use to treat pain that is not around-the-clock” becomes “Not to be taken on an ‘as needed’ basis.”
• Worsening pain (all products). A new item under “Tell your healthcare provider if you” reads, in the leaflet’s own words: “notice your pain getting worse. If your pain gets worse after you take [the medicine], do not take more … without first talking to your doctor.” It continues that patients are to talk to their doctor if pain increases, if they feel more sensitive to pain, or if they have new pain.
• Short-term use (IR products). A new item reads: “For acute (short-term) pain, you may only need to take [the medicine] for a few days. You may have some [medicine] left over that you did not use,” with a pointer to the disposal instructions.

The pregnancy item also changes “prolonged use” to use “for an extended period of time during pregnancy,” which, the leaflet says, can cause withdrawal symptoms in the newborn that could be life-threatening if not recognized and treated.

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8. What the FDA Told Clinicians and Patients

The communication contains two advice sections written by the FDA. They are summarized here as the agency’s own statements, attributed to the FDA.

The FDA’s advice to health care professionals includes: assess pain by discussing its impact on function and quality of life; when an opioid is needed and alternatives are insufficient, prescribe the lowest effective dose of an IR opioid for the shortest duration; reserve ER/LA opioids for severe and persistent pain as described in the new indication; for patients already on an ER/LA opioid who are not assessed as having severe and persistent pain, make a multimodal approach to pain management available, including mental health support, and discuss options that might include moving to an IR opioid or another treatment, with careful tapering and without abrupt discontinuation; discuss naloxone with all patients prescribed opioids and consider prescribing it for those at increased risk of overdose or with household members, including children, at risk of accidental ingestion; and, if OIH is suspected, carefully consider a dose decrease or a switch to a different opioid.

The FDA’s advice to patients and caregivers includes: take opioid medicines exactly as prescribed and talk with a health care professional before taking more or taking them more often; talk with them if pain increases, if there is more sensitivity to pain, or if there is new pain; store opioids securely, out of sight and reach of children and visitors; do not share them, and dispose of unused or expired opioids promptly or through a take-back program; seek emergency help for serious slowed, shallow or difficult breathing, severe sleepiness, or inability to respond or wake up; and ask about naloxone. The communication notes that in March 2023 the FDA approved a naloxone nasal spray for sale without a prescription, while multiple forms of naloxone remain prescription-only.

The FDA also stated that the changes recognize opioid pain medicines “remain an important treatment option in appropriate situations and that undertreatment of pain (including abrupt discontinuations and forced tapering) carries its own risks, including other morbidities and even the risk of illicit substance use for self-treatment.” Its “What is my risk?” section says that, because people respond differently to medicines, “we cannot determine how likely it is that someone will experience these side effects.” Decisions about any medicine belong with a clinician.

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9. What the Action Does Not Do

• It does not ban or restrict the sale of any opioid. It changes the labeling, the information that comes with the medicines.
• It does not replace clinical judgment. The communication says the prescribing information “cannot substitute for individual clinical judgment and talking to patients about their pain control.”
• It is not a legal limit on doses or days. The “few days” and “lowest effective dose” wording is label language for prescribers; the FDA’s documents set no numeric cap. The table itself notes that the dose and duration needed vary with the cause of pain and the individual patient.
• It does not call opioids unneeded. The FDA describes them as “an important treatment option when used as prescribed” and warns of the risks of undertreating pain.
• It does not rest on a count of how often hyperalgesia happens. The 46 cases are reports the FDA found; the agency says there may be cases it is unaware of, and the documents give no rate.

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10. Dates and Legal Status as of 18 October 2026

• 13 April 2023: Drug Safety Communication announces the required updates; NDA and ANDA holders are notified the same month.
• 15 December 2023: The FDA announces “final approval and implementation” of the required labeling updates.
• 31 July 2025: The FDA announces further class-wide opioid labeling changes on the risks of long-term use, which revise part of the 2023 wording (section 11).

Status as of 18 October 2026: final. The 2023 labeling updates were approved and implemented in December 2023, and have since been superseded in part by the 2025 changes reported on the site’s 2025 opioid long-term-use page. The FDA documents present these as required labeling updates to the drugs’ applications, not as a Federal Register rule; a check of the Federal Register through 18 October 2026 found no FDA document withdrawing or staying them.

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11. How the Action Fits Other FDA Opioid Actions

The December 2023 statement places the updates within the FDA Overdose Prevention Framework. It lists the framework’s four priorities: “supporting primary prevention by eliminating unnecessary initial prescription drug exposure and inappropriate prolonged prescribing; encouraging harm reduction through innovation and education; advancing development of evidence-based treatments for substance use disorders; and protecting the public from unapproved, diverted, or counterfeit drugs presenting overdose risks.” The Director of the FDA’s Center for Drug Evaluation and Research said that the agency understands “the importance of ensuring patients continue to have access to opioid analgesics,” and that “Approving these class-wide labeling updates facilitates safer use of these medicines and furthers our goal to reduce the risks of nonmedical use and overdose.” The statement also says the updates aim “to urge health care professionals to take a more patient-centered approach when prescribing opioid analgesic products.”

Several other 2023 FDA actions on overdose are reported on their own pages: the first over-the-counter naloxone nasal spray in March 2023, which the communication itself mentions; the import restriction on xylazine, an animal sedative found in the illicit drug supply; and the Boxed Warning update for prescription stimulants.

The story continues in 2025. The 2025 long-term-use labeling changes summarize two large FDA-required studies of long-term opioid therapy and require removal of the phrase “extended treatment period,” which the 2023 updates had placed in the ER/LA indication, from the Indications and Usage section.

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12. Primary Documents

1. U.S. Food and Drug Administration (2023). FDA updates prescribing information for all opioid pain medicines to provide additional guidance for safe use. FDA Drug Safety Communication, 13 April 2023 — fda.gov Drug Safety Communication (PDF version)
2. U.S. Food and Drug Administration (2023). Key Opioid Label Updates (former and new label wording, Tables 1–11). Attachment to the Drug Safety Communication of 13 April 2023 — fda.gov PDF
3. 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

These are agency communications rather than Federal Register rules, so they carry no FR citation or docket number.

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Key Research Papers

1. Mallama CA, Greene C, Alexandridis AA, McAninch JK, Dal Pan G, Meyer T (2022). Patient-reported opioid analgesic use after discharge from surgical procedures: a systematic review. Pain Medicine 23(1):29-44 — PubMed PMID: 34347101
2. Coyle DT, Pratt CY, Ocran-Appiah J, Secora A, Kornegay C, Staffa J (2018). Opioid analgesic dose and the risk of misuse, overdose, and death: a narrative review. Pharmacoepidemiology and Drug Safety 27(5):464-472 — PubMed PMID: 29243305
3. Guichard L, Hirve A, Demiri M, Martinez V (2021). Opioid-induced hyperalgesia in patients with chronic pain: a systematic review of published cases. Clinical Journal of Pain 38(1):49-57 — PubMed PMID: 34699405
4. Dickson-Gomez J, Krechel S, Spector A, Weeks M, Ohlrich J, Green Montaque HD, Li J (2022). The effects of opioid policy changes on transitions from prescription opioids to heroin, fentanyl and injection drug use: a qualitative analysis. Substance Abuse Treatment, Prevention, and Policy 17(1):55 — PubMed PMID: 35864522
5. Howard R, Fry B, Gunaseelan V, Lee J, Waljee J, Brummett C, Campbell D Jr, Seese E, Englesbe M, Vu J (2019). Association of opioid prescribing with opioid consumption after surgery in Michigan. JAMA Surgery 154(1):e184234 — PubMed PMID: 30422239
6. 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
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

All seven papers appear in the reference list of the FDA’s April 2023 Drug Safety Communication. The first is the systematic review behind its leftover-tablet figures; the second, by FDA authors, reviews the link between opioid dose and overdose; the third collects published cases of opioid-induced hyperalgesia; the fourth is the interview study of transitions from prescription to illicit opioids; the fifth compares opioids prescribed with opioids taken after surgery; the sixth is a randomized trial comparing opioid and non-opioid medicines for chronic back, hip or knee pain; the seventh is the 2022 federal prescribing guideline.

PubMed Topic Searches

1. PubMed: opioid-induced hyperalgesia
2. PubMed: opioid dose and overdose risk
3. PubMed: leftover opioid tablets after surgery

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Connections

• FDA Actions of 2023
• FDA and Regulation
• Opioid Long-Term Use Label Changes (2025)
• Opioids for Chronic Non-Cancer Pain
• Non-Opioid Medications for Chronic Pain
• Chronic Pain
• Opioid Overdose
• Addiction
• Over-the-Counter Naloxone (2023)
• Xylazine Import Restriction (2023)
• Stimulant Boxed Warnings (2023)

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