Illicit Fentanyl Exposure May Carry Greater Risk of Opioid-Related Harm, Study Finds
Fentanyl has become a major focus of the ongoing opioid crisis, particularly because illicitly manufactured fentanyl can expose people to unpredictable drug concentrations and combinations. A new study suggests that the source of fentanyl exposure may be an important factor when assessing the risk of opioid-related complications.
Researchers found that people exposed to fentanyl from illicit sources experienced substantially higher rates of nonfatal overdose, opioid dependence, and opioid abuse than people whose fentanyl exposure originated from medical treatment. The findings highlight the differences between medically supervised opioid exposure and exposure occurring through the illicit drug supply.
The research, published online in August 2026 in eClinicalMedicine, examined health records from hundreds of thousands of people to better understand how fentanyl source was associated with subsequent opioid-related outcomes.
What Did the Researchers Study?
The research team, led by Seungyeon Lee of The Ohio State University in Columbus, analyzed information from Epic Cosmos, a large electronic health record database. The researchers developed two groups based on patterns of fentanyl exposure.
The medical-source cohort included 85,535 people, while the illicit-source cohort included 210,193 people. Researchers then examined patterns over time and compared the likelihood of several opioid-related harmful outcomes between the groups.
Because illicit fentanyl use frequently occurs outside healthcare settings, identifying individual exposure can be challenging. Medical records do not always capture illicit drug use accurately, particularly when a person does not disclose their substance use or seeks medical attention only after an overdose or another complication.
The researchers therefore used available clinical information to characterize likely illicit fentanyl exposure and compare outcomes with those associated with medically sourced fentanyl.
Nonfatal Overdose Was More Common Among Illicit-Source Users
One of the most notable findings involved nonfatal opioid overdose.
Between 2015 and 2023, the prevalence of nonfatal opioid overdose was consistently higher among people in the illicit-source group. Overall, approximately 18.6% of individuals in that group experienced a nonfatal opioid overdose, compared with 4.3% among those in the medical-source group.
This difference does not mean that every person exposed to illicit fentanyl will experience an overdose. Rather, it demonstrates a significant difference in risk between the populations studied.
The illicit drug supply can be particularly unpredictable. People may not know the exact amount of fentanyl present in a substance, and illicitly manufactured drugs can contain other powerful substances. Variability in potency and composition can increase the possibility of accidental overdose.
Opioid Dependence and Abuse Also Showed Differences
The study also identified higher levels of opioid dependence and abuse among people in the illicit-source cohort.
Researchers observed that these conditions increased more rapidly from year to year in the illicit-source group than in the medical-source group through 2020. After 2020, however, the prevalence of opioid dependence and abuse among those exposed to illicit fentanyl began to decline.
The decline was especially noticeable for opioid dependence.
Despite the later reduction, rates remained higher in the illicit-source group than in the medical-source group. This suggests that although patterns of opioid-related harm have changed over time, people exposed to illicit fentanyl may continue to represent a population at particularly high risk.
Starting Illicit Fentanyl Was Associated With Greater Short-Term Risk
The researchers also looked at opioid-related harmful outcomes during the 30 days following fentanyl initiation.
After adjusting for relevant factors, initiation involving illicit-source fentanyl was associated with significantly higher risks compared with medical-source fentanyl initiation.
The adjusted hazard ratio was:
- 2.99 for opioid overdose
- 1.96 for opioid abuse
- 3.05 for opioid dependence
In practical terms, these figures indicate that people in the illicit-source group had considerably greater short-term risks of these outcomes than people whose fentanyl exposure began through medical sources, after statistical adjustment.
Hazard ratios should not be interpreted as an individual's personal probability of experiencing an event. They describe differences in risk between groups within the research analysis.
Why the Source of Fentanyl Matters
Medical fentanyl and illicitly manufactured fentanyl are not necessarily comparable exposures.
Fentanyl used in healthcare is administered for specific medical purposes, such as pain management or anesthesia, under controlled conditions. Healthcare professionals can determine the dose, monitor the patient, and consider other medications and health conditions that could affect safety.
Illicit fentanyl, by contrast, is produced and distributed outside regulated medical systems. Its potency and composition may vary, and people using illicit drugs may not know whether fentanyl is present at all.
Illicit fentanyl can also appear in substances that a person does not believe contain fentanyl. This creates an additional overdose risk because the individual may unknowingly consume a highly potent opioid.
Measuring Illicit Fentanyl Exposure Is Difficult
The researchers emphasized that identifying illicit fentanyl exposure in electronic health records is complicated.
Unlike medications prescribed by a healthcare professional, illicit drug use generally does not generate a standardized prescription or administration record. Information may instead come from clinical notes, toxicology results, diagnoses, emergency department visits, or other indirect indicators.
This creates challenges for researchers trying to determine how widespread illicit fentanyl exposure is and how it affects health outcomes.
Electronic health record studies can provide valuable information because they allow researchers to examine large populations over extended periods. However, the results can still be affected by limitations in how substance use is documented.
What Do the Findings Mean for the Opioid Crisis?
The findings add to evidence that illicit fentanyl exposure represents a serious public health concern.
The higher rates of overdose and opioid-related disorders observed in the illicit-source group underline the importance of prevention, early intervention, overdose education, and access to evidence-based treatment for opioid use disorder.
Reducing opioid-related deaths also requires people to have access to lifesaving resources. Naloxone, for example, can rapidly reverse an opioid overdose when administered promptly. Broader access to naloxone and education about recognizing overdose symptoms can help reduce the risk of fatal outcomes.
Treatment for opioid use disorder can also play an important role. People experiencing opioid dependence should be encouraged to seek professional medical care rather than attempting to manage the condition without appropriate support.
The Bottom Line
A large electronic health record study found that people with evidence of illicit-source fentanyl exposure had substantially higher rates of opioid-related harm than those exposed to medically sourced fentanyl.
From 2015 through 2023, nonfatal overdose was considerably more prevalent among the illicit-source group. Opioid dependence and abuse were also more common. Furthermore, illicit-source fentanyl initiation was associated with significantly elevated 30-day risks of overdose, abuse, and dependence.
The study does not establish that illicit fentanyl directly caused every adverse outcome observed. Instead, it identifies a strong association between illicit-source exposure and opioid-related harm.
As fentanyl continues to influence the opioid crisis, understanding where exposure occurs and how different patterns of use affect health may help researchers and healthcare professionals develop more effective prevention and treatment strategies.
Sources
- Lee S, et al. eClinicalMedicine. Study examining illicit-source versus medical-source fentanyl exposure and opioid-related harmful outcomes. Published online August 14, 2026.
- Epic Cosmos electronic health records database, used by researchers to analyze longitudinal clinical data.
Disclaimer: The sources above are provided for informational purposes. Readers should consult the original research publication and qualified healthcare professionals for medical interpretation or individual healthcare decisions.