FDA updates prescribing information for all opioid pain medicines to provide additional guidance for safe use

As part of its ongoing efforts to address the nation’s opioid crisis, the U.S. Food and Drug Administration (FDA) is making several updates to the prescribing information of opioid pain medicines to provide additional guidance on the use of these powerful medicines. Opioid pain medicines are an important treatment option when used as prescribed; however, they also have serious risks, including misuse and abuse, addiction, overdose, and death.

Although there has been a substantial overall decrease in the number of dispensed prescriptions for opioid pain medicines, overdose deaths involving prescription opioids have remained steady. Data also suggest that:

• many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine, although the dose and duration of treatment needed to adequately manage pain will vary based on the underlying cause and individual patient factors.
• patients who use opioid pain medicines after surgery often have unused tablets, which may pose a risk of accidental use, misuse and abuse, addiction, and overdose, including by children and teenagers.
• extended-release/long-acting (ER/LA) opioid pain medicines have unique risks and should be used only for those with severe and persistent pain.

Based on our review of available data, FDA has also determined that a new warning is needed about opioid-induced hyperalgesia (OIH), which is when 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). Although OIH can occur at any opioid dosage, it may occur more often with higher doses and longer-term use. This condition can be difficult to recognize and may result in increased opioid dosages that could worsen symptoms and increase the risk of respiratory depression.

What is FDA doing?

We are requiring several updates to the prescribing information for both immediate-release (IR) and extended release/long acting (ER/LA) opioid pain medicines (See Table of Key Opioid Label Updates). This includes stating for all opioid pain that the risk of overdose increases as the dose increases. The updates to IR opioids state these products should not 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. This may include pain occurring with a number of surgical conditions or musculoskeletal injuries. We are also updating the approved use for ER/LA opioid pain medicines to recommend they be reserved for severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate. In addition, we are adding a new warning about opioid-induced hyperalgesia (OIH) for both IR and ER/LA opioid pain medicines. This includes information describing the symptoms that differentiate OIH from opioid tolerance and withdrawal.

Information in the Boxed Warning, FDA’s most prominent 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). Other changes are also being required to several sections of the prescribing information, including to the Indications and Usage, Dosage and Administration, and Warnings and Precautions sections (See Table of Key Opioid Label Updates). We are also requiring updates to the existing patient Medication Guides to help educate patients and caregivers about these risks.

These changes to the prescribing information are designed to inform about appropriate prescribing of opioid pain medicines while also recognizing that they 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. These changes are designed to provide essential information that prescribers need to prescribe opioid pain medicines appropriately, but the prescribing information itself cannot substitute for individual clinical judgment and talking to patients about their pain control.

What is an opioid and how can it help me?

Opioid pain medicines are a class of powerful pain medicines prescribed to treat pain that does not respond well to other treatments or non-opioid pain medicines. They activate an area of nerve cells in the brain and body that block pain signals. These medicines have benefits when used appropriately, but they also have serious risks, including misuse and abuse, addiction, overdose, and death. Examples of common opioid pain medicines include codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, fentanyl, buprenorphine, and tramadol.

What should health care professionals do?

In assessing the severity of pain, discuss with the patient the impact of the pain on their ability to function and their quality of life. Assessment of pain should consider both the cause of pain and individual patient factors.

If the patient’s pain is severe enough to require an opioid pain medicine and alternative treatment options are insufficient, prescribe the lowest effective dose of an IR opioid for the shortest duration of time to reduce the risks associated with these products. Reserve increasing to higher doses only when lower doses are inadequate and the benefits of using a higher dose outweigh the substantial risks. Many acute pain conditions, such as pain occurring with a number of surgical procedures or musculoskeletal injuries, require no more than a few days of an IR opioid pain medicine.

Reserve ER/LA opioid pain medicines only for severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate. For patients currently on an ER/LA opioid who have pain severe enough to require an opioid but are not assessed as having severe and persistent pain, ensure that a multimodal approach to pain management is available, including mental health support. Discuss options for optimizing their treatment, which might include moving to an IR opioid or other alternative pain treatment, with the potential to appropriately and carefully taper the opioid but avoiding any abrupt discontinuation. Regularly reevaluate and discuss with your patients the optimum management of pain that appropriately balances the known benefits and risks, and frequently assess for development of addiction, misuse, or abuse. Inform patients of the added risks of using opioid pain medicines with benzodiazepines and other CNS depressants, and educate them on the signs and symptoms of respiratory depression.

For all patients prescribed opioid pain medicines, discuss the availability of naloxone, and consider prescribing it to those at increased risk of overdose. This may include patients who are also using benzodiazepines or other medicines that depress the central nervous system, with a history of opioid use disorder (OUD), or have experienced a previous opioid overdose. Health care professionals should also consider prescribing naloxone if the patient has household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. In March 2023, FDA approved an inhaled nasal spray version of naloxone to be sold over-the-counter without a prescription.

Be aware that the symptoms of OIH, a condition where opioids cause an increase in pain (called hyperalgesia) or an increased sensitivity to pain (called allodynia), are distinct from opioid tolerance and withdrawal and can be difficult to recognize (see Additional Information for Health Care Professionals). If a patient is suspected to be experiencing OIH, carefully consider an appropriate decrease in dose of the current opioid pain medicine or safely switching them to a different opioid product, if tolerated. Advise patients about the risk of OIH and tell them to never increase the opioid dosage without first consulting a health care professional, because this could worsen the pain and increase the risk of respiratory depression.

What should patients and parents/caregivers do?

Always take your opioid medicines exactly as prescribed. Do not take more of the medicine or take it more often than prescribed without first talking to your health care professional. Talk with them if your pain increases, you feel more sensitive to pain, or if you have new pain, especially from touch or other things that are not usually painful such as combing your hair.

Store your opioid pain medicines securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Do not share these medicines with anyone else, and immediately dispose of unused or expired opioids or take them to a drug take-back site, location, or program. If provided, use the prepaid mail-back envelopes included with the prescription.

Seek emergency medical help or call 911 immediately if you or someone you are caring for experiences symptoms of respiratory problems, which can be life-threatening. Signs and symptoms include serious slowed, shallow, or difficult breathing, severe sleepiness, or not being able to respond or wake up.

Talk to your health care professionals about the benefits of naloxone, which can reverse and opioid overdose, and how to obtain it. Your health care professional can give you a prescription for naloxone. Additionally, in most states and the District of Columbia you can obtain naloxone from a pharmacy under a standing order that takes the place of an individual prescription. Some states also allow you to obtain naloxone without a prescription from a community-based program or pharmacy. Check with your state Health Department for more information. In March 2023, FDA approved an inhaled nasal spray version of naloxone to be sold over-the-counter without a prescription while multiple forms of naloxone remain available as prescription only.

What did FDA find?

Despite substantial declines in the rates for opioid pain medicine dispensing, 1 prescription opioid medicine-involved overdose deaths have remained relatively steady over time, with 16,706 deaths in 2021. 2 However, these statistics likely underestimate the role of prescription opioids in contributing to overall opioid-related overdose deaths. Data suggest some patients who are prescribed opioid pain medicines may progress to nonmedical use of opioids and other controlled substances, contributing to the number of opioid-related overdoses. 3 The impact of the opioid crisis extends beyond deaths and includes health consequences and harm to families. 4,5

Evidence suggests that patients getting opioid pain medicines for acute pain are often prescribed a larger quantity than needed, 6 resulting in unused tablets. When not properly disposed of, these unused opioid tablets provide opportunities for nonmedical use, accidental exposure, and overdose. 7 Data also strongly suggest that the risk of overdose increases as the prescribed dosage of opioid pain medicines increases, 8 and this risk can occur at any point during treatment.

Opioid pain medicines also have been associated with other complications such as OIH. We identified 46 cases describing hyperalgesia and allodynia when opioid pain medicines were being used to treat pain, including eight with short-term use and 38 with longer-term use. These cases include only those submitted to the FDA Adverse Event Reporting System or those found in the medical literature,9 so there may be cases about which we are unaware (see Background and Data Summary). The cases involved a range of opioid pain medicines, including morphine, hydromorphone, and fentanyl/fentanyl analogs most commonly. Other possible causes of the increased pain were excluded, such as worsening of disease. Cancer was the most reported underlying condition being treated. Patients reported improvement in pain after stopping opioid pain medicines. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been suggested.

What is my risk?

Like all medicines, opioid pain medicines can have side effects, even when used correctly as prescribed. It is important to know that people respond differently to medicines depending on their health, the diseases they have, genetic factors, other medicines they are taking, and many other factors. As a result, we cannot determine how likely it is that someone will experience these side effects when taking opioid pain medicines. Talk to your health care professional if you have questions or concerns about the risks of taking opioid pain medicines.

How do I report side effects from opioid pain medicines?

To help FDA track safety issues with medicines, we urge patients and health care professionals to report side effects involving opioid pain medicines or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page.

How can I get new safety information on medicines I’m prescribing or taking?

You can sign up for email alerts about Drug Safety Communications on medicines or medical specialties of interest to you.

Table of Key Opioid Label Updates

Facts about Opioid Pain medicines

• Opioid pain medicines are powerful prescription medicines that can help manage pain when other treatments and medicines are not able to provide enough relief. However, opioid pain medicines also carry serious risks, including misuse and abuse, addiction, overdose, and death.
• There are two main categories of prescription opioid pain medicines. Immediate-release (IR) products are usually intended for use every 4-6 hours as needed for acute pain. Extended-release/long-acting (ER/LA) opioid pain medicines 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 alternative treatment options are inadequate, depending on the individual product and patient.
• Opioid pain medicines are available in many different forms, including tablets, capsules, lozenges, sublingual tablets, transdermal patches, nasal sprays, and injections.
• Common side effects of opioid pain medicines include drowsiness, dizziness, nausea, vomiting, constipation, physical dependence, and slowed or difficult breathing.
• The risk of opioid addiction, misuse, or abuse is increased in patients with a personal or family history of substance use disorder or mental illness.
• Naloxone is an opioid reversal medicine used to treat an opioid overdose or possible overdose and can help prevent death. Naloxone is widely available according to individual state’s requirements or guidelines. Consider co-prescribing naloxone with all opioid prescriptions for those at increased risk of opioid overdose. In March 2023, FDA approved the inhaled nasal spray version of naloxone to be sold over-the-counter without a prescription.

Additional Information for Health Care Professionals

• As part of its ongoing efforts to address the nation’s opioid crisis, FDA is making several updates to the opioid analgesics’ prescribing information to provide additional guidance on prescribing these powerful medicines. Although there has been a substantial overall decrease in the number of dispensed prescriptions for opioid analgesics, prescription opioid-related overdoses have not similarly decreased. Data suggest that:
  • many acute pain conditions treated in the outpatient setting, such as pain occurring with a number of surgical procedures or musculoskeletal injuries, require no more than a few days of an opioid pain medicine, although dose and duration of treatment needed to adequately manage pain will vary based on the underlying cause and individual patient factors.
  • outpatient opioid pain medicine use after surgery often results in unused tablets, and when not properly disposed of these unused medicines provide opportunities for nonmedical use, accidental exposure, and overdose.
  • extended-release/long-acting (ER/LA) opioid pain medicines have unique risks due to their properties and should be reserved for those with severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate.
  • increased pain intensity despite increasing opioid pain medicine doses
  • decreased pain intensity in response to a decrease in opioid pain medicine doses
  • hypersensitivity to non-painful stimuli (in the absence of opioid tolerance or withdrawal)

  Additional Information for Patients and Caregivers

  • As part of its ongoing efforts to address the nation’s opioid crisis, FDA is making several updates to the prescribing information of opioids used for pain to provide additional guidance to health care professionals prescribing these powerful medicines, which have serious risks, including misuse and abuse, addiction, overdose, and death.
  • FDA is also adding a new warning about opioid-induced hyperalgesia (OIH), which is when 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).
    • OIH is a condition that can occur at any dosage of an opioid, but it may occur more often with higher doses and longer-term use
    • Talk to your health care professional if your pain increases, if you feel more sensitive to pain, or if you have new pain after taking your opioid pain medicine

    Background and Data Summary

    Opioid-involved overdose deaths have risen steadily over the past 15 years, with a dramatic increase between 2017 (47,600 deaths) and 2021 (80,411 deaths). 2 Although most opioid-involved deaths are due to illicit fentanyl and fentanyl analogs, 2 several statistics help frame the context in which FDA is taking action to update the prescribing information for opioid pain medicines. Despite substantial declines in the rates of opioid pain medicine dispensing, falling from 81.3 prescriptions per 100 persons in 2012 to 43.3 prescriptions per 100 persons in 2020, 1 prescription opioid-involved overdose deaths have remained relatively steady over time, with 16,706 deaths in 2021. 2 These mortality statistics likely underestimate the role of prescription opioid pain medicines in contributing to overall opioid-related overdose deaths.

    Data suggest that some patients prescribed opioid pain medicines may transition to nonmedical use of opioids and other controlled substances. In one study conducted between 2019 and 2021, researchers led in-depth interviews with 148 participants from three different states who reported using heroin, illicit fentanyl, or prescription opioid pain medicines nonmedically. 3 Of those participants, 90 percent reported their initial exposure involved prescription opioid pain medicines, nearly half (48%) of whom obtained them through a prescription. Many reported using opioids nonmedically for many years. Some study participants reported that their use of illicit opioids may have been influenced by policies and prescribing practices that unintentionally limited access to prescription opioids in inappropriate ways, e.g., rapid discontinuation of prescribed opioids.

    The impact of the opioid crisis extends beyond mortality and includes associated morbidity and societal costs. Among Americans 12 and older, 5.6 million (2%) reported in 2021 having an opioid use disorder (OUD) in the past year. 7 Health consequences of non-fatal, opioid-involved overdoses may include acute complications, such as opioid-induced respiratory depression, and more serious, chronic complications, such as brain injury. 4 The impacts on children and their families include an increased risk of mental health problems, drug use, development of substance use disorder, accidental opioid poisoning, and loss of a parent to an opioid overdose. 5

    Evidence suggests opioid pain medicines continue to be overprescribed for many patients with some acute pain conditions. A systematic review of studies published through 2019 examined patient-reported outpatient opioid pain medicine use after surgery, finding that among studies that reported on excess tablets, 25 percent to 98 percent of total tablets prescribed were reported as excess, with most studies reporting between 50 percent and 70 percent excess tablets. 6 Studies show that many patients report having leftover opioids after surgery. 11,12, 13 , For many acute and chronic pain conditions, other non-opioid treatments, including both non-pharmacologic and pharmacologic, have been found to be effective. For a number of conditions, non-opioid medicines may be just as effective as opioid pain medicines. 14,15

    Opioid-induced Hyperalgesia (OIH)
    Opioid pain medicines have been associated with opioid-induced hyperalgesia (OIH), a condition where opioids cause an increase in pain (called hyperalgesia) or an increased sensitivity to pain (called allodynia). Increases in pain typically occur following a dose increase and resolve quickly following proper diagnosis and management of the condition.

    We identified 46 patients describing hyperalgesia and allodynia when opioid pain medicines were being using to treat pain, including eight with short-term and 38 with longer-term use. These cases include only those submitted to the FDA Adverse Event Reporting System or those found in the medical literature, 9 so there may be cases about which we are unaware. The cases involved a range of opioid pain medicines, including most commonly morphine, hydromorphone, and fentanyl/fentanyl analogs. Cancer was the most reported underlying condition being treated. Other possible causes were excluded such as worsening of disease. Patients reported improvement in pain after stopping opioid pain medicines. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been suggested.

    References

    1. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, November 10, 2021, U.S. Opioid Dispensing Rate Maps, https://www.cdc.gov/overdose-prevention/data-research/facts-stats/us-dispensing-rate-maps.html.
    2. National Institute on Drug Abuse, February 9, 2023, Drug Overdose Death Rates, https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates.
    3. Dickson-Gomez J, S Krechel, A Spector, M Weeks, J Ohlrich, HD Green Montaque, J Li, July 21, 2022, The effects of opioid policy changes on transitions from prescription opioids to heroin, fentanyl and injection drug use: a qualitative analysis, Subst Abuse Treat Prev Policy, 17(1):55, doi: 10.1186/s13011-022-00480-4.
    4. Office of the Assistant Secretary for Planning and Evaluation, 2019, Non-Fatal Opioid Overdose and Associated Health Outcomes: Final Summary Report, https://aspe.hhs.gov/reports/non-fatal-opioid-overdose-associated-health-outcomes-final-summary-report-0.
    5. Winstanley E, A Stover, September 2019, The Impact of the Opioid Epidemic on Children and Adolescents, Clin Ther, 41(9):1655–1662, epub ahead of print July 11, 2019, doi: 10.1016/j.clinthera.2019.06.003.
    6. Mallama CA, C Greene, AA Alexandridis, JK McAninch, G Dal Pan, T Meyer, January 3, 2022, Patient-Reported Opioid Pain medicine Use After Discharge from Surgical Procedures: A Systematic Review, Pain Med, 23(1):29–44. doi: 10.1093/pm/pnab244. PMID: 34347101.
    7. Substance Abuse and Mental Health Services Administration, 2022, Key substance use and mental health indicators in the United States: Results from the 2021 National Survey on Drug Use and Health (HHS Publication No. PEP22-07-01-005, NSDUH Series H-57), Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, https://www.samhsa.gov/data/report/2021-nsduh-annual-national-report
    8. Coyle, D. T., Pratt, C. Y., Ocran-Appiah, J., Secora, A., Kornegay, C., & Staffa, J. (2018). Opioid pain medicine dose and the risk of misuse, overdose, and death: A narrative review. Pharmacoepidemiol Drug Saf, 27(5), 464-472. doi:10.1002/pds.4366.
    9. Guichard, L., Hirve, A., Demiri, M., & Martinez, V. (2021). Opioid-induced Hyperalgesia in Patients with Chronic Pain: A Systematic Review of Published Cases. Clin J Pain, 38(1), 49-57. doi:10.1097/ajp.0000000000000994.
    10. Mattson, C.L., et al., Drug Overdose Deaths in 28 States and the District of Columbia: 2020 data from the State Unintentional Drug Overdose Reporting System (SUDORS). SUDORS Data Brief, No 1, Atlanta, GA: Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, 2022. Figure 3. Accessed Jan 23, 2023, available from: https://www.cdc.gov/overdose-prevention/data-research/facts-stats/sudors-dashboard-fatal-overdose-data.html.
    11. Thiels CA, DS Ubl, KJ Yost, SC Dowdy, TM Mabry, HM Gazelka, RR Cima, EB Habermann, September 2018, Results of a Prospective, Multicenter Initiative Aimed at Developing Opioid-prescribing Guidelines After Surgery, Ann Surg, 268(3):457–468. doi: 10.1097/SLA.0000000000002919. PMID: 30004924.
    12. Howard R, B Fry, V Gunaseelan, J Lee, J Waljee, C Brummett, D Campbell Jr, E Seese, M Englesbe, J Vu, 2019, Association of Opioid Prescribing With Opioid Consumption After Surgery in Michigan, JAMA Surg, 154(1):e184234, epub ahead of print January 16, 2019, doi: 10.1001/jamasurg.2018.4234.
    13. The NO PAin Investigators, 2022, Effect of a Postoperative Multimodal Opioid-Sparing Protocol vs Standard Opioid Prescribing on Postoperative Opioid Consumption After Knee or Shoulder Arthroscopy: A Randomized Clinical Trial, JAMA, 328(13):1326–1335, doi: 10.1001/jama.2022.16844.
    14. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2022. MMWR Recomm Rep. 2022; 71:1-95.
    15. Krebs EE, A Gravely, S Nugent, AC Jensen, B DeRonne, ES Goldsmith, K Kroenke, MJ Bair, S Noorbaloochi, 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, doi: 10.1001/jama.2018.0899.

    Related Information

    • Drug Safety Podcast
    • FDA Overdose Prevention Framework
    • Opioid Medications
    • Opioid Overdose
    • Information about Naloxone
    • State Health Departments
    • Naloxone Access by State
    • Disposal of Unused Medicines: What You Should Know
    • Lock it Up: Medicine Safety in Your Home
    • The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective
    • Think It Through: Managing the Benefits and Risks of Medicines

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