Complicating the Opioid Epidemic: Scientists Estimate Fentanyl Has Hundreds of Millions of Chemical Variants

Expanded library of known variants, new research efforts aid the fight against fentanyl.

While Covid has dominated the news for the last two years, a separate epidemic claims the lives of more than 100,000 Americans each year. Fentanyl, a synthetic substance initially created as a painkiller but evolved into a lucrative and dangerous street narcotic, lies at the heart of the opioid crisis.

Aside from the thousands of lives lost each month, the two share a crucial trait: the power to change—or be changed—into something unexpected, creating a difficult challenge. The first step in protecting oneself is just being aware of the danger.

Fentanyl variants: the threat

Covid has developed variants like Omicron, which are effective in bypassing the body’s defenses.

Fentanyl has variations as well—chemical structures that have a greater impact on the body, making it more lethal and addicting. In order to avoid discovery, evade the law, and earn more money, enterprising chemists throughout the globe are busily experimenting in makeshift labs, creating new and illicit versions of the painkiller—estimated to be 100 times more effective in its basic form than morphine.

PNNL is expanding the library of data on known fentanyl variants, keeping first responders such as hazardous materials workers safe in the field. Credit: Gorodenkoff | Shutterstock.com

Scientists at the Department of Energy’s Pacific Northwest National Laboratory estimate that fentanyl has hundreds of millions of possible chemical variants, known as analogs. Every variant that becomes real at the hands of an enterprising chemist spells risk.

“New forms of drugs are appearing constantly,” said PNNL scientist Richard Ozanich, an analytical chemist who is addressing the fentanyl crisis with funding from the Department of Homeland Security. “That means that sometimes, we don’t know exactly what we’re looking for; a new form may not yet be on the radar of law enforcement.”

Fentanyl library saves lives

First responders rely on databases, commonly known as libraries, of chemical structures of known fentanyl variants. It’s like a set of chemical fingerprints of harmful drugs and other hazardous substances. Keeping the fentanyl library up to date is hugely important. Drug dealers and unscrupulous chemists are constantly modifying compounds in small but consequential ways—enough to create substances that evade detection, allow dealers to evade prosecution and still pack a deadly punch.

Many of the illicit substances that make their way to the United States originate in Mexico and China. Their creators work on analogs that are more addictive or are easier to make. Or they create forms that can be diluted or “cut” more efficiently, boosting profits, or used to augment counterfeit pills and other illicit substances.

Each addition to the fentanyl catalog is a step toward safety for law enforcement, paramedics and others. Credit: Sara Levine | Pacific Northwest National Laboratory

Every variant that goes unlisted gives criminals a loophole—an opportunity to skirt the law.

“Even if a compound isn’t on the list yet, it can kill you,” said Ozanich, who noted that some forms are so potent that an amount no larger than a grain of salt can be deadly.

Ozanich leads a project funded by the Department of Homeland Security Science and Technology Directorate to help close the gap. His team is updating the libraries that police, hazardous materials teams and other first responders use to identify and understand hazardous substances they encounter. Police, firefighters and others typically carry portable instruments that tap into these databases, giving officials instant insight into what they have encountered.

PNNL has added about 50 chemical structures to the libraries, which also include information on drugs like heroin, cocaine and methamphetamine.

A bigger library lessens the chance that a police officer, firefighter, paramedic or others will face a dangerous unknown substance they can’t identify.

“Law enforcement and other officials need to make decisions quickly in dangerous situations. Do we need to cordon off the area? Are we safe? Is there a danger to others? Improving the information to make those decisions quickly is the focus of our efforts,” Ozanich said.

“Knowing what hazard you’re up against in the field allows you to take appropriate action to protect yourself and the public,” he added.

Going beyond the library

Other PNNL scientists are utilizing powerful computers and innovative computational chemistry methods to predict potential fentanyl analogs that have yet to be created—potential additions to the library even before they reach the market. The study is part of an attempt to ultimately lessen dependence on a library generated using physical sample analysis results.

Instead, PNNL scientists are investigating methods to predict and rank potential chemical structures in a sample based on an understanding of the fundamental scientific principles at work. This would allow for early identification of threats from alternative forms of fentanyl or other sources, rather than depending only on what is already known.

Scientists are exploring millions of possible fentanyl structures, measuring their chemical properties to determine which are most likely to appear and what their data look like—to go beyond known threats and to detect unknown threats early and quickly. Credit: Sara Levine | Pacific Northwest National Laboratory

The fentanyl research fits squarely into PNNL’s wheelhouse to search for, detect and measure substances or phenomena of interest. These include explosive residues, rare gases produced in nuclear explosions, dark matter, traces of other illicit drugs, hints of radiation, and dangerous chemicals like ricin and sarin. Researchers actively pursue new ways to detect or—ideally—to predict and prevent such threats before they exist.

“What this capability comes down to is proactive situational awareness—that is, the possibility to get ahead of the threat in time to help law enforcement and first responders mitigate it effectively,” said Kabrena Rodda, a senior scientist at PNNL who leads a number of projects to counter chemical threats.

“As this capability matures, we’re excited about the potential to go beyond mere recognition of a threat to applying it in novel applications to keep people safe,” Rodda added.

Assuring accuracy, safety in the field

The library update is part of a broader two-year project Ozanich is heading to assess the performance of detection equipment used by emergency responders around the nation. PNNL has brought together 14 manufacturers of 21 key instruments that first responders and others use to detect and measure fentanyl. Those instruments cover nearly all the forms of fentanyl found on the streets today.

Ashley Bradley works in a specialized laboratory hood where substances’ chemical properties are measured. The PNNL team uses such information to compile a library of data on known fentanyl variants. Credit: Andrea Starr | Pacific Northwest National Laboratory

Through the effort, the current work by Ozanich and colleagues will filter down to nearly every fentanyl incident confronted by police and others anywhere in the nation.

The project dovetails with another DHS-funded project that Ozanich has led, focusing on fentanyl standards. He brought together more than 100 scientists, first responders, drug enforcement officials, equipment manufacturers and others under the auspices of ASTM International to develop three new laboratory standards. Without proper standards, police and paramedics would be at more risk as they do their jobs.

Two standards address the performance of equipment and methods to test for fentanyl and related compounds in the field. A third standard is designed as a guide for first responders encountering fentanyl in the field. That standard benefitted from considerable input from first responders, with whom PNNL has a strong relationship, in part through the Northwest Regional Technology Center.

?Scientists Kai-For Mo and Ashley Bradley help each other into personal protective equipment before working in the fentanyl laboratory. Credit: Andrea Starr | Pacific Northwest National Laboratory

One law enforcement official who has worked with Ozanich is Detective Sergeant Pakorn Patimetha of the Hazardous Materials Response Unit of the New Jersey State Police.

“Every day, we see different varieties of fentanyl being mixed into all types of drugs and illicit pills,” said Patimetha, who majored in biochemistry in college before going into teaching and then law enforcement. Patimetha estimates that in the last five years, the percentage of narcotics samples sent to the state’s crime laboratory that contain fentanyl has skyrocketed from five to more than 90 percent.

“A crime scene can be chaotic. We need to identify fentanyl quickly and accurately in the field to make sure that everyone stays safe and hazardous evidence is properly secured,” added Patimetha. “It’s important to keep first responders involved, because we can explain what it’s like in the field, in real-world conditions. Rich gets first responders involved. We give our input directly to make sure that the methods are valid and that they work like we need them to work.”

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