The increasing distribution of illicitly manufactured fentanyl (IMF) across the United States, and the sharp rise in overdose deaths linked to this drug, are causing more concern about a growing threat to public health and safety.

According to a report published online August 25 in Morbidity and Mortality Weekly Report (MMWR), the number of drug products obtained by law enforcement that tested positive for fentanyl (fentanyl submissions) increased by 426% from 2013 through 2014. Deaths related to synthetic opioids (excluding methadone) increased by 79% during that period.

"An urgent, collaborative public health and law enforcement response is needed to address the increasing problem of IMF and fentanyl deaths," said the report's authors, led by R. Matthew Gladden, PhD, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention (CDC).

Pharmaceutical fentanyl, a synthetic opioid 50 to 100 times more potent than morphine, is approved for the management of surgical/postoperative pain, severe chronic pain, and breakthrough cancer pain. IMF, which is unlawfully produced fentanyl obtained through illicit drug markets, is commonly mixed with or sold as white powder heroin.

Starting in 2013, the production and distribution of IMF increased to unprecedented levels. In 2015, the Drug Enforcement Administration (DEA) and the CDC issued nationwide alerts identifying increases in fentanyl-related overdose deaths in multiple states.

The current report documents changes in synthetic opioid–related overdose deaths among 27 states where death certificates consistently report drugs involved in overdoses. These changes were highly correlated with fentanyl submissions, but not with fentanyl prescribing, which remained relatively stable.

High-Burden States

The report identified eight states where increases in fentanyl submissions and synthetic opioid deaths were primarily concentrated. In these "high-burden" states, the synthetic opioid crude death rate increased 174%, and the rate of reported fentanyl submissions increased by 1000%.

These high-burden states were located in the Northeast (Massachusetts, Maine, and New Hampshire), the Midwest (Ohio), and the South (Florida, Kentucky, Maryland, and North Carolina). Increases in synthetic opioid deaths in high-burden states disproportionately involved non-Hispanic white men aged 25 to 44 years.

The strong correlation between increases in fentanyl submissions, primarily driven by IMF, increases in synthetic opioid deaths, mostly related to fentanyl, and uncorrelated stable fentanyl prescriptions rates supports the hypothesis that IMF is driving the increases in fentanyl deaths, according to the report's authors.

"The high potency of fentanyl and the possibility of rapid death after fentanyl administration, coupled with the extremely sharp 1-year increase in fentanyl deaths in high-burden states, highlights the need to understand the factors driving this increase," the authors write.

The authors note a number of limitations to their findings. One is that because synthetic opioid deaths include those involving drugs other than fentanyl, the absolute number of synthetic opioid deaths should be considered "a proxy" for the number of fentanyl deaths.

Also, whereas drug submissions vary over time and from region to region, the findings are restricted to 27 states, and testing for fentanyl deaths might vary across jurisdictions.

Ohio and Florida

Data on fentanyl-related overdose deaths in Ohio and Florida further suggest that the problem of IMF is rapidly expanding, according to a second report also published in the current issue of MMWR. The study highlights a sharp increase in fentanyl deaths between 2013 and 2015 in these two states that parallels an increase in fentanyl submissions.

The study was carried out by the University of Florida and the Ohio Department of Public Health, in collaboration with the CDC, and was written by Alexis B. Peterson, PhD, Epidemic Intelligence Service and the National Center for Injury Prevention and Control, CDC, and colleagues.

Investigators found that from 2013 to 2014, fentanyl submissions increased 494% in Florida and 1043% in Ohio. This, they note, was "concurrent" with a 115% increase in fentanyl deaths in Florida and a 526% increase in Ohio. They also saw a "sharp increase" in fentanyl submissions and fentanyl deaths in Florida from December 2014 to February 2015.

In contrast, fentanyl prescription rates (per 1000 population) for the full year (2013-2014) increased only 5% in Florida and declined 7% in Ohio.

Death Demographics

Dr Peterson and colleagues note that the demographics of fentanyl-related deaths now "mirror" those of people dying from heroin overdose. For example, in Florida, fentanyl deaths increased almost 2.5 times faster among men (163%) than women (68%), with the most rapidly increasing rate among those aged 14 to 34 years. In contrast, US death rates involving prescription opioids are highest in an older group, those aged 45 to 54 years.

Researchers also uncovered evidence that the percentage of fentanyl deaths in which the victim tested positive for other illicit substances, such as cocaine and heroin, increased significantly over the study period.

In Ohio, factors associated with fentanyl deaths included a current diagnosis of a mental health disorder and a recent release from an institution, such as jail, a rehabilitation facility, or a hospital.

"Persons recently released from an institution are at particularly high risk for opioid overdose because of lowered opioid tolerance resulting from abstinence during residential treatment or incarceration," they write. "Interventions such as provision of naloxone and continuation of medication-assisted treatment after release have been shown to be effective for this group."

Increased naloxone access is "critical" given fentanyl's potency and the possibility of its causing rapid death, they add.

Their findings, the authors say, suggest that the surge in fentanyl deaths in Florida and Ohio is closely related to increases in the local IMF supply as opposed to diverted pharmaceutical fentanyl.

"Distinguishing whether an overdose involves IMF or [pharmaceutical fentanyl] is critical for targeted interventions because overdose risk profiles differ."

Warning System

The relationship between fentanyl deaths and fentanyl submissions suggests that law enforcement testing data on drug cases could act as an "early warning system" to identify changes in the illicit drug supply, the authors write.

Multidisciplinary strategies from public health agencies, harm reduction communities, emergency medical services, law enforcement, and treatment services for substance use disorders might have the greatest impact on public health, given the close relationship between fentanyl mortality and confiscation of IMF, they continue.

The report pertaining to Florida and Ohio also had limitations, many of them similar to those of the first report. Among those cited was the underestimation of the numbers and rates of fentanyl deaths, as not all overdose deaths were tested for fentanyl.

August 31 is International Overdose Awareness Day, an event that aims to raise awareness globally that deaths from overdoses are preventable.

MMWR Morb Mortal Wkly Rep. Published online August 26, 2016. First report, full text; Second report, full text