Opioid Analgesics FAERS Adverse Events and REMS: 2021–2026 Trends

The landscape of prescription opioid surveillance is a critical junction of regulatory oversight, clinical risk management, and public health policy. As part of our ongoing pharmacovigilance series, this analysis examines the multi-year reporting trends of adverse events associated with prescription opioid analgesics in the FDA Adverse Event Reporting System (FAERS) from 2021 through the second quarter of 2026.

By analyzing raw data from the FAERS database and aligning it with the regulatory requirements of the FDA's Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS), this article provides biopharma professionals, payers, and clinical safety teams with a quantified, evidence-based view of prescription opioid safety signaling.

Short Answer

In our analysis of the FAERS database from 2021 through 2026, adverse event reports naming a prescription opioid analgesic fell sharply from 84,677 reports in 2021 to 26,137 reports in 2025—a 69.1% decline. Suspect-opioid reports (where the opioid was designated as the primary or secondary suspect drug) followed an identical path, dropping from 84,539 to 25,811. Fatal outcomes among these suspect-opioid reports decreased from 10,030 in 2021 to 5,855 in 2025 (a 41.6% decline).

The frequency of the MedDRA reaction term "overdose" fell by 94.3%, declining from 22,373 instances in 2021 to 1,272 in 2025, while reports containing respiratory depression or respiratory failure terms remained comparatively stable (falling only 22.5% from 604 to 468). These trends must be interpreted within the context of the Opioid Analgesic REMS (first approved in 2018 as an expansion of the 2012 ER/LA REMS) and the MATE Act of 2023, which has standardized prescriber education. However, safety professionals must recognize that FAERS data represents passive surveillance and does not capture the broader shift toward illicit synthetic fentanyl.

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Opioid Analgesic FAERS Reporting Trends: 2021–2026

To understand the trajectory of prescription opioid safety signaling, we computed the annual aggregates of total FAERS reports, reports naming a prescription opioid, suspect-role counts, fatal outcomes, and specific MedDRA reaction terms.

Our dataset includes the following prescription opioid analgesics: oxycodone, hydrocodone, fentanyl (transdermal/transmucosal), morphine, oxymorphone, hydromorphone, tramadol, codeine, methadone, tapentadol, and buprenorphine (indicated for pain). It excludes illicitly manufactured compounds and buprenorphine/methadone formulations indicated solely for opioid use disorder (OUD) treatment, keeping the focus strictly on prescription pain management.

Multi-Year Safety Signal Table

*Note: 2026 data represents a partial year count based on the available openFDA FAERS snapshot through June 10, 2026.

Analyzing the Decline in Opioid Reports

The data demonstrates a clear and consistent downward trend in the volume of adverse events submitted to the FDA involving prescription opioids. Total annual reports naming an opioid fell from 84,677 in 2021 to 26,137 in 2025.

Several factors contribute to this decline:

1. Decreasing Prescribing Rates: Nationwide initiatives, state-level prescription drug monitoring programs (PDMPs), CDC prescribing guidelines, and restrictive payer formulary edits have consistently reduced the total volume of prescription opioids dispensed in the United States.
2. Shift to Alternative Therapies: Payers and clinicians have increasingly pushed toward non-opioid pharmacotherapies (such as NSAIDs, gabapentinoids, and topical agents) and non-pharmacologic interventions for chronic pain management, reducing the patient exposure pool.
3. Reporting Normalization: Adverse event reporting often spikes during the initial years of a public health crisis or when new regulatory actions are introduced. As clinical awareness of opioid risks has become deeply institutionalized, spontaneous reporting of known side effects by clinicians and manufacturers has naturally normalized.

The Disparity Between Report Volume and Fatal Outcomes

While overall opioid-named reports dropped by 69.1% between 2021 and 2025, fatal outcomes associated with these reports did not decline at the same rate. In 2021, there were 10,030 fatal outcomes out of 84,539 suspect-opioid reports (an 11.9% fatality rate within reports). By 2025, fatal outcomes stood at 5,855 out of 25,811 suspect reports (a 22.7% fatality rate).

This rising proportion of fatal outcomes suggests that while mild and moderate adverse events (such as constipation, nausea, or mild sedation) are being reported far less frequently, severe events resulting in death remain a persistent signal. This highlights that despite lower overall exposure, the intrinsic risks of respiratory depression and fatal toxicity in vulnerable patient populations remain highly concentrated.

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Drug-by-Drug Signaling Analysis

To understand how individual active substances contribute to the overall opioid adverse event profile, we analyzed the individual reporting patterns for key drugs in this class.

1. Oxycodone

Oxycodone (found in brand-name products like OxyContin and generic combinations like oxycodone/acetaminophen) remains the single most frequently cited substance in the prescription opioid dataset. In 2021 it appeared in roughly 70% of opioid-named reports, and even after the class-wide decline it still accounted for about 29% of opioid-named reports in 2025 (a single report can list multiple substances, so per-substance shares need not sum to 100%).

The reporting profile is dominated by accidental therapeutic errors, drug abuse/dependence signals, and severe gastrointestinal side effects. Fatal outcomes related to oxycodone, although declining in absolute numbers alongside overall prescribing, continue to represent a significant proportion of the class signal, particularly when co-reported with other central nervous system (CNS) depressants.

2. Hydrocodone

Hydrocodone (predominantly prescribed as hydrocodone/acetaminophen or Vicodin) is historically the most widely prescribed immediate-release opioid in the United States. In the FAERS dataset, hydrocodone exhibits a high volume of reporting but a lower rate of fatal outcomes compared to oxycodone.

Common adverse event codes for hydrocodone include accidental overdose, drug ineffective (often representing tolerance issues), and hepatic injury (due to the acetaminophen component in combination products). The scheduling change of hydrocodone combination products from Schedule III to Schedule II in late 2014 initiated a long-term decline in volume that continues to be reflected in the 2021–2026 reporting levels.

3. Fentanyl (Prescription Formulations)

Prescription fentanyl (including transdermal patches like Duragesic and transmucosal formulations like Actiq or Fentora) is indicated strictly for the management of severe chronic pain in opioid-tolerant patients or breakthrough cancer pain.

Because of its extreme potency, prescription fentanyl exhibits a very high fatality-to-report ratio within the FAERS database. Major signaling themes include:

• Accidental Exposure: Reports of children or caregiver contact with discarded transdermal patches.
• Application Errors: Concomitant heat exposure (e.g., heating pads or hot tubs) accelerating drug absorption.
• Formulation Defects: Reports of gel reservoir leakage in older patch designs.

Safety professionals must separate these prescription-specific signals from the mass-market public health reports of illicit fentanyl toxicity.

4. Tramadol

Tramadol is a synthetic, centrally acting analgesic that combines mu-opioid receptor agonism with serotonin and norepinephrine reuptake inhibition. In the FAERS database, tramadol exhibits a unique adverse event profile characterized by high reporting rates of:

• Seizures: Often occurring at therapeutic doses, particularly in patients taking concomitant antidepressants (SSRIs, SNRIs, or TCAs).
• Serotonin Syndrome: A life-threatening condition driven by drug-drug interactions.
• Hypoglycemia: An under-recognized metabolic adverse event.

Because it was long perceived as a "safer" or "weaker" opioid, tramadol's reporting rates remained elevated in the early part of the decade, but they have steadily declined as clinical guidelines have highlighted these non-opioid toxicities.

5. Methadone

Methadone, when prescribed for pain management (as opposed to opioid treatment programs), presents unique pharmacokinetics, including a long and unpredictable half-life (ranging from 8 to 59 hours) and a tendency to prolong the QTc interval.

In the FAERS database, methadone reports frequently code for cardiac arrhythmias, Torsades de Pointes, and delayed respiratory depression. Due to these complex safety variables, methadone represents a disproportionately high number of fatal outcomes relative to its prescribing volume, highlighting the critical need for electrocardiogram (ECG) monitoring and slow dose titration.

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MedDRA Reaction Term Analysis: Overdose vs. Respiratory Depression

To understand the clinical nature of the reported events, we isolated specific Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PTs) within the opioid dataset. We focused on "overdose" (including accidental, intentional, and unspecified overdose) and "respiratory depression" (including respiratory depression, respiratory failure, and acute respiratory distress).

The Overdose Reporting Collapse

The most dramatic shift in the dataset is the collapse of reports containing the MedDRA "overdose" term. These fell from 22,373 in 2021 to 1,272 in 2025—a 94.3% absolute decline, far steeper than the 69.1% drop in opioid-named reports overall.

This steep reduction reflects changes in how acute poisoning and substance use disorder events are captured. Historically, many prescription opioid reports in FAERS included terms related to misuse, abuse, and accidental overdose. The sharp drop indicates a significant cleanup of the prescription surveillance channel, likely because the vast majority of acute opioid overdoses in the United States have shifted to illicit synthetic fentanyl and heroin, which are not captured in FAERS because they do not involve regulated, manufactured drug products.

The Persistence of Respiratory Depression

In contrast, reports containing MedDRA terms for "respiratory depression" and "respiratory failure" remained remarkably flat. There were 604 reports in 2021, peaking slightly at 611 in 2022, before settling at 468 in 2025.

Unlike "overdose," which can represent behavioral misuse or suicide attempts, "respiratory depression" is the direct, primary pharmacological mechanism of opioid-induced lethality. The persistence of this signal—even as prescribing and overall reporting drop—underscores that therapeutic doses of opioids continue to cause life-threatening respiratory events. This is particularly true in patients with pre-existing risk factors, such as:

• Concomitant use of benzodiazepines, gabapentinoids, or muscle relaxants.
• Underlying respiratory conditions (such as severe COPD or obstructive sleep apnea).
• Genetic variations in metabolic rate (e.g., CYP2D6 ultra-rapid metabolizers taking codeine or tramadol).

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The Opioid Analgesic REMS Framework

The FDA has long recognized that standard labeling and boxed warnings are insufficient to manage the risks of prescription opioids. The primary regulatory vehicle for managing these risks is the Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS).

Historical Evolution of the REMS

• July 9, 2012: The FDA approves the Extended-Release and Long-Acting (ER/LA) Opioid Analgesic REMS. This program focused exclusively on high-dose, long-acting formulations (such as OxyContin, MS Contin, and transdermal fentanyl patches), which were deemed to present the highest risk of abuse and accidental overdose.
• September 18, 2018: Recognizing that immediate-release (IR) outpatient opioids (such as generic Vicodin or Percocet) represented the vast majority of initial patient exposures and subsequent dependency, the FDA formally expanded the program into the Opioid Analgesic REMS. This unified framework brought both immediate-release and extended-release prescription pain products under a single safety umbrella.
• September 2018: Alongside the expanded REMS, the FDA issued the FDA Education Blueprint for Health Care Providers Involved in the Treatment and Monitoring of Patients with Pain (commonly the "FDA Blueprint"), the curricular standard for the manufacturer-funded accredited continuing education (CE) that the REMS makes available at little or no cost. The Blueprint has since been revised to incorporate safe-disposal guidance, but the REMS itself does not require prescribers to complete it.
• June 27, 2023: The training requirement of the MATE Act (Section 1263 of the Consolidated Appropriations Act of 2023, which was signed into law on December 29, 2022) takes effect, independently requiring new and renewing DEA registrants to complete at least eight hours of substance-use-disorder training—accredited REMS CE can satisfy part of this requirement.

Key Elements of the REMS Program

Unlike highly restrictive REMS programs that utilize Elements to Assure Safe Use (ETASU) to control distribution (such as the clozapine or thalidomide programs), the Opioid Analgesic REMS relies primarily on accredited professional education:

1. Shared System REMS: The program is administered as a single, shared system supported by all manufacturers of brand-name and generic prescription opioid analgesics. This prevents clinicians from having to navigate different portals for different products.
2. Prescriber Education: The REMS requires manufacturers to make training available to all healthcare providers involved in the treatment and monitoring of patients with pain. This training is delivered via independent, accredited Continuing Education (CE) providers and must align with the FDA Blueprint.
3. The MATE Act Alignment: Under Section 1263 of the Consolidated Appropriations Act of 2023 (the Medication Access and Training Expansion Act, or MATE Act), all DEA-registered prescribers must complete at least 8 hours of training on the treatment and management of patients with opioid or other substance use disorders. Accredited training completed under the FDA Opioid Analgesic REMS satisfies this DEA requirement.
4. Patient Counseling Tool: The REMS mandates that prescribers provide patients with a Patient Action Plan or counseling guide, emphasizing safe storage, the risks of concomitant alcohol or benzodiazepine use, and the importance of having naloxone (Narcan) readily available in the household.

The FDA Education Blueprint Details

The accredited training mandated by the REMS is structured around the FDA Education Blueprint. This curriculum is designed to standardize how clinicians assess, initiate, modify, and discontinue opioid therapy. The training covers several core areas:

1. Assessing Pain and Assessing Risk:

   • Understanding the pathophysiology of pain and distinguishing between acute, chronic, and cancer pain.
   • Conducting a thorough patient history, including physical, psychological, and social factors.
   • Utilizing validated screening tools (such as the Opioid Risk Tool or SOAPP-R) to evaluate a patient's risk of substance use disorder, misuse, or diversion.
   • Identifying patient-specific risk factors for opioid-induced respiratory depression (e.g., renal or hepatic impairment, advanced age, or sleep apnea).

2. Initiating and Managing Opioid Therapy:

   • Utilizing non-pharmacologic and non-opioid pharmacotherapies as first-line options.
   • Deciding when to initiate opioid therapy, selecting the appropriate molecule, strength, and formulation (IR vs. ER/LA).
   • Establishing realistic, measurable functional and pain-reduction goals with the patient.
   • Dosing safely, understanding Morphine Milligram Equivalents (MME), and managing patient-specific titration schedules.
   • Implementing monitoring strategies, including periodic urine drug testing (UDT), checking state PDMPs, and conducting pill counts.

3. Counseling Patients and Caregivers:

   • Educating patients on the proper administration of the drug, including avoiding chewing, crushing, or dissolving extended-release formulations.
   • Warning against the co-ingestion of alcohol or other CNS depressants, particularly benzodiazepines, which dramatically increase the risk of fatal respiratory depression.
   • Emphasizing safe storage practices, such as using lockboxes, to prevent accidental ingestion by children or diversion by adolescents.
   • Instructing on safe disposal methods, such as utilizing community take-back programs or FDA-approved flush lists.
   • Counseling on the role, availability, and administration of naloxone for emergency overdose reversal.

4. Tapering and Discontinuing Opioids:

   • Recognizing the signs of opioid use disorder and understanding when a patient is no longer experiencing therapeutic benefit.
   • Developing safe, individualized tapering schedules to minimize severe withdrawal symptoms.
   • Managing physical dependence vs. psychological addiction, and referring patients to specialized addiction treatment (e.g., Medication-Assisted Treatment with buprenorphine or methadone) when necessary.

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State-Level Prescribing Mandates and Payer Strategies

While the FDA REMS establishes the national standard for education, actual prescribing behavior is heavily governed by state-level legislation and commercial payer policies.

State Prescribing Limits

Beginning in 2016, many states enacted laws limiting the duration and dosage of initial opioid prescriptions for acute pain. Common statutory limits include:

• 7-Day Limits: Enacted in states like Massachusetts, New York, and North Carolina for initial acute pain prescriptions in opioid-naive patients.
• 3-to-5-Day Limits: Enacted in states like Florida, Kentucky, and Arizona, particularly for pediatric patients or dental procedures.
• MME Ceilings: Statutes in states like Ohio and Washington that require formal pain specialist consultation or additional documentation if a prescriber exceeds a specific MME threshold (e.g., 80 or 120 MME per day).

These state-level limits have functioned as an administrative barrier, forcing clinicians to document clinical necessity and preventing the automatic dispensing of high-volume prescriptions.

Payer-Led Access Controls

Commercial insurers and PBMs have implemented parallel access controls under the pharmacy benefit:

• Quantity Limits: Restricting immediate-release opioids to a maximum of 90 or 120 tablets per month without prior authorization.
• Prior Authorization for ER/LA Formulations: Requiring documentation that the patient has failed non-opioid therapies and immediate-release opioids, and that they have signed a patient-provider opioid agreement.
• Concomitant Drug Blocks: Utilizing real-time pharmacy claims edits to automatically block or flag the simultaneous dispensing of an opioid and a benzodiazepine to prevent fatal interactions.
• Mandated Naloxone Coprescribing: Automatically adding a copay or requiring the concurrent dispensing of naloxone with any opioid prescription exceeding 50 or 90 MME daily.

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Pharmacovigilance Limitations of FAERS Data

While the safety signals in FAERS are invaluable for regulatory decision-making, safety directors and market access teams must interpret these numbers with caution. The FDA explicitly lists several limitations regarding the use of FAERS data:

1. No Estimate of Incidence: FAERS is a passive surveillance database based on voluntary reporting by clinicians and consumers, as well as mandatory reporting by manufacturers. Because the total number of patients exposed to the drug (the denominator) is not captured in the system, FAERS reports cannot be used to calculate the absolute incidence or rate of adverse events.
2. No Confirmed Causality: Naming a specific drug product in a FAERS report does not prove that the drug caused the adverse event. Many reports involve patients with complex comorbidities, polypharmacy, and advanced disease states, making it difficult to isolate a single causative agent.
3. Under-Reporting and Over-Reporting: Minor side effects are routinely under-reported. Conversely, highly publicized drugs or classes (such as opioids) often experience temporary reporting spikes due to increased public and clinical awareness (known as the Weber effect).
4. Data Duplication: A single adverse event may be reported multiple times—for instance, by the treating physician, the dispensing pharmacist, the patient, and the drug manufacturer. While the FDA attempts to deduplicate entries using patient demographics and event dates, duplicate cases remain within the raw data extracts.
5. Exclusion of Illicit Substances: FAERS only tracks FDA-regulated, legally manufactured drug products. Consequently, the massive volume of overdoses and deaths driven by illicit synthetic fentanyl, street heroin, and counterfeit pressed pills is completely absent from this dataset. This explains why FAERS opioid death reports show a decline while CDC national drug overdose mortality figures have remained near record highs.

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Frequently Asked Questions (FAQ)

Does a falling number of opioid FAERS reports mean opioid harm is declining?

Not necessarily. The decline in FAERS reports reflects a reduction in prescribing volume, a shift of acute overdoses to illicit street drugs, and reporting normalization among clinicians. Because FAERS is a passive reporting database, it cannot measure the true incidence of opioid-related harm. CDC mortality data shows that overall opioid-related deaths remain extremely elevated, driven primarily by illicit synthetic fentanyl, which is not captured in FAERS.

What is the difference between the ER/LA Opioid REMS and the current Opioid Analgesic REMS?

The original ER/LA Opioid REMS (established in 2012) applied only to extended-release and long-acting formulations, which were considered high-risk. In September 2018, the FDA expanded the program to include all immediate-release (IR) outpatient opioid analgesics, renaming it the Opioid Analgesic REMS. This change recognized that immediate-release products represent the vast majority of initial patient exposures and subsequent addiction risks.

Are prescribers legally required to complete the Opioid Analgesic REMS training?

Under the FDA REMS itself, the training is voluntary for prescribers; the FDA cannot legally mandate continuing education as a condition of prescribing. However, the federal MATE Act of 2023 made at least 8 hours of training on substance use disorders mandatory for all DEA registrants upon renewal. Because accredited REMS courses satisfy this DEA requirement, prescriber participation has increased significantly.

Does the Opioid Analgesic REMS utilize Elements to Assure Safe Use (ETASU)?

No. Unlike high-risk REMS programs that restrict drug distribution to certified specialty pharmacies or require registry enrollment (such as those for thalidomide or isotretinoin), the Opioid Analgesic REMS relies on provider education, patient counseling tools, and clinical blueprints. It does not restrict the distribution of prescription opioids to specific pharmacies or require patient registries.

How does the MATE Act of 2023 relate to the FDA Opioid Analgesic REMS?

The MATE Act requires all DEA-registered practitioners to complete at least 8 hours of training on substance use disorders. Rather than creating a separate training mandate, the DEA allows practitioners to satisfy this requirement by completing accredited courses that align with the FDA Opioid Analgesic REMS Education Blueprint, effectively merging the two training standards.

Why do some highly potent opioids show lower absolute report counts in FAERS?

Potent opioids like prescription fentanyl or methadone are prescribed in much lower volumes than common immediate-release agents like hydrocodone or oxycodone. Consequently, their absolute report counts are lower, but their ratio of serious or fatal outcomes per report is significantly higher, indicating a concentrated risk profile.

Sources

1. U.S. Food and Drug Administration (FDA). Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS). Current approved program and modification letters. https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/opioid-analgesic-risk-evaluation-and-mitigation-strategy-rems
2. U.S. Food and Drug Administration (FDA). FDA's Opioid Analgesic REMS Education Blueprint for Health Care Providers Involved in the Treatment and Monitoring of Patients with Pain, Center for Drug Evaluation and Research (CDER), September 2018 (later revised to add safe-disposal guidance). https://www.fda.gov/media/99496/download
3. FDA Adverse Event Reporting System (FAERS). openFDA Adverse Event API and Data Extracts, US FDA. Raw CSV partitions 2021–2026. https://open.fda.gov/apis/drug/event/
4. Opioid Analgesic REMS Program. Frequently Asked Questions for Healthcare Providers, accredited CE consortium. https://www.opioidanalgesicrems.com/faq1.html
5. U.S. Centers for Disease Control and Prevention (CDC). Clinical Practice Guideline for Prescribing Opioids for Pain, CDC Prevention and Control Reports. https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm

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Disclaimer: This article provides independent regulatory and market access analysis for biopharma professionals and does not constitute clinical, medical, or legal advice.