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In the latest edition of its National Vital Statistics Report, released this month, the Center for Disease Control and Prevention identified the specific drugs most frequently associated with overdose deaths in the United States from 2011-2016.

Oxycodone ranked first in 2011, and heroin took the top spot for the next four years. However, in 2016, the title changed hands again, this time to a drug that’s making headlines across the country for its lethality and potency: fentanyl.

“The rate of drug overdose deaths involving fentanyl and fentanyl analogs doubled each year from 2013 through 2016, from 0.6 per 100,000 in 2013 to 1.3 in 2014, 2.6 in 2015, and 5.9 in 2016,” according to the report. In 2016, fentanyl accounted for 18,335 overdoses, or 28.8 percent of all overdose-related deaths. That number is staggering, given that fentanyl accounted for only 8,251 deaths in 2015, 4,223 in 2014, 1,919 in 2013 and 1,615 in 2012.

Why the increase? The report points to an obvious culprit: “Nearly one-third of drug overdose deaths involving fentanyl also mentioned heroin,” according to the authors, while “two in five overdose deaths involving cocaine also mentioned fentanyl.” As crackdowns across the country on the prescription of pharmaceutical narcotics have slowed the pill epidemic, opioid addicts have turned to illegal drugs like heroin as a substitute. As a result, dealers at various levels of the illegal drug trade have begun “cutting” their products, usually with fentanyl produced in Chinese or Mexican labs and shipped illegally into the United States.

To combat the problem, however, it’s important to understand exactly what it is. The drug itself has become a buzzword in news articles and broadcasts, but few people understand its history or its consumption.

Born in a laboratory

According to “The Fentanyl Story,” a 2016 article in The Journal of Pain (the official publication of the American Pain Society), fentanyl’s roots can be traced back to the 1950s and Dr. Paul Janssen, who established Janssen Pharmaceutica in 1953. According to the journal Anesthesia and Analgesia, one of his interests was creating potent, effective, rapid-acting analgesics to treat the many pain problems of the time,” building off of the molecular structure of meperidine, which was used in conjunction with morphine for pain management during those years.

Because penetration of the central nervous system by those two drugs was problematic, their onset was slowed, and so “they began working with meperidine, rather than morphine, as the parent molecule in the production of newer and better compounds because it was much less complex a molecule and thus easier to manipulate,” according to “The Fentanyl Story.” By adding to and replacing elements of the meperidine chemical structure, they began to create a better class of narcotics that were more potent and better penetrated the blood-brain barrier, leading to a faster onset of analgesic effects.

By 1957, they had synthesized phenoperidine, “25 times more potent than morphine and more than 50 times more potent than meperidine in most animals in which it was tested,” according to the Anesthesia and Analgesia article. It was, at the time, the most potent opioid in the world and began to be prescribed in European markets, where it still has some uses today. Fentanyl was born in the Janssen lab in 1960, and the researchers discovered it was “more than 10 times more potent than phenoperidine and 100 to 200 times more potent than morphine in most animal models.” It had the fastest onset of action and “highest therapeutic index” for pain ever measured in an opioid, and its unique construction meant that its potency was best achieved through intravenous use, because 60 to 70 percent of the compound was destroyed when it was taken orally.

Physicians immediately saw its potential, and according to the 2014 book “The Wondrous Story of Anesthesia,” it was used in combination with a number of other intravenous drugs “in attempts to create a type of total intravenous anesthesia in the 1960s and 1970s.” Anesthesiologist Gorge de Castro of Belgium worked with a team from Janssen to determine that large doses of intravenous fentanyl could serve as a stress-free anesthesia — “a drug or combination of drugs that provided deep anesthesia with minimal or no alteration of cardiovascular dynamics and also blocked the increase in the stress-responding hormones that normally occurred with surgical stimulation,” according to “The Fentanyl Story.”

His work made little impact, however, and in the United States, Food and Drug Administration approval of fentanyl was problematic; University of Pennsylvania anesthesiology professor Dr. Robert Dripps “felt that fentanyl was too potent and caused rigidity. This, he thought, would result in many patients needing to be tracheally intubated and would lead to many abuse problems,” the aforementioned Anesthesia and Analgesia article states.

Big Pharma takes an interest

Janssen met with Dripps, however, and a compromise was reached: Fentanyl would be approved, but only when used in a 50:1 ratio with the tranquilizer droperidol. Approval came in 1968, and the first drug to contain Fentanyl, Innovar, was introduced to the American market. Four years later, fentanyl was approved for sale on its own in minute doses, but as advances in cardiovascular surgery began to reveal that high-dose narcotics produced stable dynamics and unconsciousness, fentanyl began to be used in place of morphine.

Many of the problems associated with high-dose morphine were alleviated by substituting fentanyl, and in the 1980s, sales increased dramatically — tenfold in 1981, the first year the patent expired. In some ways, “The Fentanyl Story” explains, it can be tied to the increase in opioid use: “The marked increase in fentanyl usage throughout the world in the 1980s resulted in a number of events that would further improve the popularity of fentanyl, lead to other fentanyl-like compounds, increase the use of other opioids, and begin an entire new field of novel opioid drug delivery development.”

So-called “super fentanyl” drugs were developed for use in wild animal immobilization and anti-terrorism; trans-dermal fentanyl patches were introduced; and two companies in particular developed oral lozenges — lollipops, as they were referred to. By that point, Janssen had been absorbed by Johnson & Johnson, and the young pharmaceutical company Azar Corporation turned to fentanyl’s developers to market Duragesic, the transdermal patch that showed marked pain management prospects for post-surgical candidates and chronic pain sufferers. The result was profound: “Duragesic proved to be one of the most successful analgesic pharmaceutical products ever developed, with sales in 2004 (its last year of patent life) exceeding $2.4 billion,” according to “The Wondrous Story of Anesthesia.”

In the years since, a number of companies have developed new delivery systems to expedite, streamline and make more efficient the manner of sedation and narcotization. From the child-friendly Oralet lollipops to nasal sprays to sublingual tablets, fentanyl has proven a valuable tool in pain management across all areas of medicine, but as with other opioids, it’s also been problematic.

From medicine to abuse

FDA approval of Oralet, for example, was “held up for months in 1993 because of concerns about the possibility of unintentional overdoses of fentanyl,” according to “The Fentanyl Story.” Overdoses on the drug began to occur soon after its 1972 approval, mostly through “misuse and illicit uses,” and as new ways of administration have developed over the years, the potential for abuse and addiction has increased.

Although certain safeguards were put in place, the production of fentanyl by black market profiteers circumvents any safety measures on legal prescription fentanyl. In a report earlier this month, The Associated Press reported that “much of the illicit fentanyl consumed in the U.S. originates in China, but is often smuggled through Mexico. Mexican cartels have also been known to produce the drug from precursor chemicals mainly imported from China.” While Chinese officials at this fall’s G-20 Summit pledged to crack down on the manufacture of fentanyl in China, those measures, if enacted, won’t have an immediate impact.

Besides, according to Deputy Chief Ron Talbott of the Blount County Sheriff’s Office, the floodgates have already opened.

“I’ve been assigned to narcotics since 1995, and heroin would come and go around here,” he said. “We would see it pop up, but then it would be gone, and when it would come (into the market), people would be afraid of it and wouldn’t want any part of it, so it took a really long time to catch on. But then we went through the prescription pill epidemic, and it came back, because the folks are addicted, and they feel like they need something.

“Once we heard about it coming back, we would hit the street and go out and buy it, do some searches, make some buy busts, make some arrests. We would react, and react strong, but there was a day that cam where we just woke up, and fentanyl was here. And once it was here, that was it. We’ve heard from other law enforcement across the state that we’d wake up one day and be eat up with it, no matter how bad you’re fighting to keep it out.”

Cutting agent and additive

Fentanyl isn’t a product that addicts pursue on its own. Although some may have experience with the old Duragesic patches (junkies swap tales of tearing them open and consuming the gel), fentanyl’s reputation as a serious narcotic used in anesthesia still holds sway. Very few, if any, addicts go out of their way to purchase fentanyl specifically. They end up buying it anyway, however, because drug traffickers use it as a cutting agent.

Very few batches of street drugs are 100 percent pure; to maximize profit, traffickers mix other substances in with their products to stretch the amount and sell more. Often it’s benign, like baby laxative; other times, it’s anything they can find under the kitchen sink, although economic wisdom says that a poisoned product isn’t likely to encourage repeat business.

With fentanyl, Talbott said, heroin can be cut without losing its potency.

“Any fentanyl we see on the streets isn’t pharmaceutical grade that someone’s gotten from a doctor with prescribing instructions on it; it’s something that’s come from overseas and gone through two or three hands and been mixed in somebody’s kitchen,” he said. “Probably the best way to understand is that, for instance, you’ve got a gallon-sized Ziploc bag of flour that’s just under halfway full.

“You open two Sweet’N Low packets, put them in the flour, which represents your drug, and shake it up, and those Sweet’N Low packets represent fentanyl. By the time you end up getting and using it, you might get 10 percent fentanyl, and the next dose might not contain any fentanyl. The next dose might be only 1 percent fentanyl, but the next one might be 90 percent. There are no set ratios, and these guys don’t have a clue as to how much they’re taking.”

And because of fentanyl’s potency, a little bit goes a long way, he added.

“I don’t know how you would even try to legitimately mix up such a small amount of fentanyl to cut something with,” he said.

A killer high

On the local level, any fentanyl seized through busts is already mixed in with other substances, and often those who consume it don’t even realize they’ve done so. If they’re lucky, says Travis Pyle — director of medical services at Cornerstone of Recovery — they live to figure it out.

“They just know they’ve overdosed and lived, and the ones that come through realize they probably did something that had fentanyl in it,” Pyle said. “A lot of them just end up dead, and we discover later on the autopsy report.”

What frightens Talbott the most are the demographics: Law enforcement is seeing a shift toward younger victims of overdoses and younger addicts who wind up strung out on heroin and in danger of shooting up a batch mixed with fentanyl.

“What used to be full addiction on the needle happening to people who are 30 or older is now happening to people who are 20 years old or younger,” he said. “That’s what’s so hard to believe. You would think, ‘OK, it takes a long time to get to that level,’ but these are 20-year-olds that are junkies. It’s beyond me how something that lethal, that strong and that powerful can take over their lives.”

Pyle knows — that’s the nature of addiction. The substance may earn a lot of headline ink, but it’s ultimately irrelevant from an addiction treatment perspective. At Cornerstone, any patient addicted to opiates is subjected to a similar regimen at the outset of treatment: around-the-clock medical supervision and detoxification medications including a three- to five-day stepdown regiment of Subutex and “comfort meds” like Robaxin and Clonodine.

Detox is just the first step; the goal of treatment at facilities like Cornerstone is to address the need addicts have to get high in the first place. And while Pyle and his coworkers strive toward that goal, Talbott and his are working tirelessly to prevent fentanyl from claiming even more lives.

“I think we’re somewhere between the tip and the crest, and I do feel like it’s going to get worse before it gets better,” he said. “There are a hundred reasons for that, but the two big ones are recovery and incarceration. A lot of people aren’t going to go into recovery until they’re incarcerated. That’s when they’ve hit bottom and decide they’ve got to do something. At the same time, in many cases our recovery systems are full.”

Fortunately, at Cornerstone of Recovery, the doors are always open.

“We can get them the help that they need,” Pyle said. “They don’t have to end up as one of those statistics. If they want help, we can give that to them. All they have to do is make that choice and that initial phone call.”