Keeping Up With the Fentanyls

Fentanyls are on the move. According to a recent study from the Centers for Disease Control and Prevention (CDC), the synthetic opioids have been cutting a deadly path across the northeastern United States. In New England alone, the fentanyl overdose death rate reached 22.5 per 100,000 in 2017 – about 15 times higher than the prevailing rate throughout the western United States. It’s an alarming statistic that both exacerbates the toll of the US’s opioid crisis and the pressure toxicology labs are under to study it.

But if this rapid migration of deadly medication wasn’t difficult to keep up with already, fentanyls are also evading analysts through their chemistry. Due to an inexpensive and flexible production process, unique versions of the synthetic opioids are regularly cooked up by illicit chemists, creating new dangers for consumers and new headaches for toxicologists.

“You have new physical analogues popping up every single day [and] that can be really challenging,” says Sabra Botch-Jones, an assistant professor of forensic chemistry at the Boston University School of Medicine.

So, with the weight of the nation’s opioid crisis on their shoulders, how can lab analysts keep up with these fatally fickle drugs? Well, to begin with, they’re going to need the best equipment.

Fully equipped

“Sometimes what we're seeing in living individuals is going to be a very low-level drug within a biological sample, such as blood or urine,” Botch-Jones says. “And so we need instrumentation that is incredibly sensitive, so that we can actually see down into the very low nanogram per milliliter.”

But with fentanyl chemistry constantly in flux, the amount of analytical equipment needed to test every variation can grow as big as the fentanyl catalogue itself.

“You can develop your method and you can have a huge number of fentanyl analogues,” Botch-Jones continues, “and then, as the new ones come up, you have to really judge what you are going to keep in your method. But if you keep everything in there, that's a lot of money that goes into that method.”

Judging which pieces of equipment to keep and which to buy is one way to stay ahead of the fentanyl game, but as Botch-Jones says, these meticulous machines can come with hefty price tags. 

“The most sensitive instrumentation is very expensive,” she says. “And so not all laboratories can just go out and lay down half a million dollars on a piece of equipment. So that's another challenge that we're dealing with: where are we getting the resources to have the instrumentation for our laboratories?”

Fortunately, if two toxicology labs are friendly enough, these instruments could be shared. “If they don't have the instrumentation within their laboratory to do some structural elucidation to determine what a molecule is, then they are left to reaching out to their scientific community for assistance,” Botch-Jones says.

Getting a reference

But sourcing the right equipment is only part of the battle. No matter how high-tech, no analytical machine can detect a fentanyl derivative if it doesn’t know what it’s looking for. So, toxicology labs have to go right to the source.

“We work with manufacturers of certified reference material who will synthesize the drug so that we can develop analytical methods that can actually report our results,” Botch-Jones explains.

How can these reference material manufacturers keep up with the ever-expanding list of fentanyl derivatives? Well, fortunately they have the CDC on their side, which this year produced its traceable opioid material (TOM) kits, a library of 44 solutions to support laboratory detection of emerging opioids in the US. From Furanyl fentanyl HCl to Norfentanyl-13C6 oxalate, these TOM kits contain all the frequently used fentanyl flavors, free of charge. It’s an invaluable catalogue for cash-strapped labs, but it only covers the most commonly used analogues. To test for the new and the niche, labs still have to pay.

“Unfortunately for accredited laboratories, if they can’t validate the method, they can't report it out,” says Botch-Jones. “So even though they have the technology to identify it, they may not be able to actually report it out without having the material that can validate their method.”

So, if low on funds and stuck with an unfamiliar chemical, what can a lab do? Well, they can do what anyone in 2019 does when stuck for answers: use a search engine.

Finding fentanyl

“[One] option is to go down more of a predictive modelling route,” says Edward Sisco, a research scientist at the National Institute of Standards and Technology (NIST). “So using algorithms, can you predict whether [a sample is] a fentanyl, a cathinone, or a cannabinoid?”

It may sound like science fiction, but such speculative search engines are already in use. “One of my colleagues at NIST has done one for GC-MS (gas chromatography–mass spectrometry),” Sisco explains. “They can take GC-MS spectra and predict the structure of the unknown fentanyl that’s not in their library.”

Using a method termed hybrid similarity search,the NIST tool, free to download as of 2018, contains an algorithm for searching chemical databases that can recognize new fentanyl analogues even if there are no matches in the existing databases.

“Hybrid search is not the silver bullet that will solve the opioid epidemic, but it is a very useful tool,” Sandra Rodriguez-Cruz, a senior research chemist with the Drug Enforcement Administration's Southwest Laboratory in California, clarified in a press statement. “If you have a difficult molecule, it can speed up your workflow significantly.”

Ultimately, as the illicit fentanyl engineers adapt to toxicologists’ methods, an ever-expanding arsenal of useful tools may be the only defense analysts have. And as fentanyls have largely supplanted heroin on the street market, it’s not just lab toxicologists that are in need of such tools, but law enforces as well.

“I think in the next five years we will see some big jumps towards the ability to have in-field mass specs that have decent resolution and sensitivity,” says Sisco.

As synthetic opioids are easily inhaled, law enforcement and other first responders at a scene put themselves at risk of exposure and accidental overdoses. With these dangers in mind, Sisco developed his own lateral flow immunoassays tool at NIST, so law officials can rapidly detect fentanyls and their fumes as soon as possible.

“So the sensitivity is actually quite good with those,” Sisco says. “In some cases, we've seen it better than GC-MS.”

“They are specific, [which] is one of the potential drawbacks,” he clarifies. “They do work for some of the analogues, but not all. So depending what you're specifically looking for, they may or may not be useful for your task.”

Of course, Sisco’s in-field fentanyl detectors were never intended to replace the bigger lab-based machines; “obviously, there is always going to be some sort of follow up,” he adds. But their inclusion in analysts’ arsenals helps to extend toxicologists’ capabilities right to the first responders of fentanyl use. And with every corner of the fentanyl crisis covered, and a little more cash and collaboration thrown in for good measure, the toxicologists might just be able to stay ahead of the game.