(CNN) — Synthetic opioids such as fentanyl have overtaken prescription opioids as the No. 1 killer in the opioid epidemic, according to a new report.

The report, published Tuesday in the journal JAMA, calculated the number and percentage of synthetic opioid-related overdose deaths in the United States between 2010 and 2016 using death certificates from the National Vital Statistics System. The researchers found that about 46% of the 42,249 opioid-related overdose deaths in 2016 involved synthetic opioids such as fentanyl, while 40% involved prescription drugs.

That’s more than a three-fold increase in the presence of synthetic opioids from 2010, when synthetic drugs were involved in approximately 14% of opioid-overdose deaths.

“It’s certainly concerning. I think that it tracks very closely with the increased availability of illicit synthetic opioids that are coming into the US,” said Christopher Jones, director of the National Mental Health and Substance Use Policy Laboratory at the Substance Abuse and Mental Health Services Administration and a lead author of the report.

The report did not include those death certificates that did not specify drug type, meaning the absolute number of opioid-related overdose deaths was likely underestimated, according to Jones.

“Somewhere between 15 and 25% of the overdose deaths don’t list specific drugs,” Jones added. “So the actual numbers are likely higher.”

Fentanyl is a synthetic opioid that is 50 to 100 times more powerful than other opioids such as morphine, heroin and oxycodone, according to Lindsay LaSalle, senior staff attorney for the nonprofit Drug Policy Alliance, who was not involved in the most recent report.

Though fentanyl can be prescribed by a physician for pain relief, the vast majority of overdose cases are thought to be the result of illicit production and distribution.

“Almost all of the increases in overdose deaths are attributed to illicitly manufactured fentanyl, not pharmaceutical fentanyl that has been misused or diverted. And we know that because the number of prescriptions for pharmaceutical fentanyl has remained relatively stable over the past decade, whereas seizures of illicitly manufactured fentanyl has skyrocketed,” LaSalle said.

“So it really is due to illicitly manufactured fentanyl that is entering the market and that is essentially being mixed with heroin so that you have an adulterated product that people aren’t aware of, so their risk of overdose increases substantially,” she added.

This is the first time synthetic opioids have surpassed prescription opioids — such as oxycodone and hydrocodone — and heroin as the primary cause of opioid overdose-related deaths, according to the report.

In 2016, when 46% of opioid overdose-related deaths involved synthetic opioids and 40% involved prescription drugs, 37% involved heroin, according to the report.

“Those of us who work in hospital settings are under siege in dealing with the fallout from the opioid epidemic. We have seen the increase in fentanyl first hand, so these findings make sense,” said Dr. Kevin Hill, director of the Division of Addiction Psychiatry at Beth Israel Deaconess Medical Center in Boston, who was not involved in the recent report.

“Increased potency may mean a more intense high, but it also means an increased risk of overdose,” Hill added. “It is likely that potency will continue to rise as dealers and manufacturers try to outdo one another.”

There are a number of reasons behind the recent increase in fentanyl use in the United States. Perhaps the biggest is cost. Synthetic opioids, which can be produced en masse in a laboratory, are much cheaper to make than other types of opioids, which are ultimately derived from poppy plants, according to LaSalle.

“Synthetic opioids are significantly easier to manufacture. They’re manufactured in a lab, as opposed to fields of poppies that have to be cared for and cultivated and farmed,” LaSalle said.

The synthetic drugs are primarily made outside of the country, according to LaSalle.

“Illicitly manufactured fentanyl is almost exclusively made in China,” she said. “It’s then shipped, broadly speaking, to Mexico, where it’s added to the heroin supply before it enters the United States as a cost-saving measure.”

After entering the United States, synthetic opioids often end up in places like the Midwest and Northeast, where the white powder form of the drug can easily be mixed with the white powder form of heroin or cocaine.

“In those parts of the country, you have a white powder heroin that you can mix fentanyl into pretty easily,” LaSalle said. “Whereas on the West Coast, you have a black tar heroin, which is very difficult to mix the white powder into. So you just don’t see the same distribution of fentanyl on the West Coast as in these other places.”

The new report also found that nearly 80% of deaths involving synthetic opioids also involved other drugs, including other opioids (50%), cocaine (22%), benzodiazepines (17%), alcohol (11%) and antidepressants (5%).

This suggests that the vast majority of synthetic opioid-related deaths are probably the result of either intentional drug mixing or contamination of other drugs with fentanyl, according to Jones.

“Initially when synthetic opioids showed up in the US, it was largely mixed with heroin. But now we’re seeing it mixed with cocaine, methamphetamines and other substances of abuse. And in the last couple of years we’ve seen this proliferation of counterfeit tablets that are made to look like commonly abused prescription drugs,” Jones said.

“And that’s particularly concerning because people who are not regularly exposed to opioids are going to be at an increased risk of the respiratory depressant effects of opioids because they have no tolerance.”

Another reason for the deadly nature of synthetic opioids such as fentanyl has to do with its rapid onset of action.

“Fentanyl overdoses occur over a matter of minutes, as opposed to heroin overdoses that occur over a matter of hours. So the response time for a heroin overdose is much longer, and there’s enough time to call 911 to get EMS out there,” LaSalle said.

But with fentanyl overdoses, “many times, the needle is still inserted in people’s arms. That is how quickly it happens.”

Consequently, those who may be at risk for fentanyl exposure — as well as their loved ones — should always have access to the opioid reversal agent naloxone and know how to use it, according to Jones.

“Raising awareness generally is really important — that’s why we wanted to get the research out there, to raise awareness among clinicians and others who might be interacting with people who use drugs to raise awareness about the unpredictability and toxicity in the drug supply,” Jones said.

“Certainly, increasing access to naloxone and ensuring that there are adequate doses of naloxone available is a critical part of the public health response.”

This message echoes Surgeon General Jerome Adams’ advisory a month ago urging nearly all Americans to become familiar with the life-saving benefits of naloxone:

“For patients currently taking high doses of opioids as prescribed for pain, individuals misusing prescription opioids, individuals using illicit opioids such as heroin or fentanyl, health care practitioners, family and friends of people who have an opioid use disorder, and community member who come into contact with people at risk for opioid overdose, knowing how to use naloxone and keeping it within reach can save a life.”

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