THURSDAY, Sept. 14, 2023 (HealthDay News) -- The "fourth wave" of the U.S. overdose crisis involves the use of illicit fentanyl mixed with stimulants such as cocaine or methamphetamine, and it’s killing people in droves.

The proportion of U.S. overdose deaths involving both fentanyl and stimulants jumped by more than 50-fold since 2010, from 0.6% in 2010 to more than 32% in 2021, a new study shows.

“Fatal overdose involving both fentanyl and stimulants is on the rise,” said study author Chelsea Shover, an assistant professor-in-residence at the UCLA David Geffen School of Medicine in Los Angeles. “Not surprisingly, but very important is that it's really an overdose crisis as opposed to just an opioid crisis now.”

The first wave of the U.S. opioid crisis was marked by an increase in deaths from prescription opioids in the early 2000s, and the second wave was driven by a shift to the illegal opioid heroin starting in 2010. Around 2013, an increase in fentanyl overdoses heralded the third wave, and the fourth wave began in 2015 and continues to rise.

Fentanyl is a man-made opioid that is up to 50 times stronger than heroin and 100 times stronger than the prescription opioid morphine.

For the study, published Sept. 14 in the journal Addiction, researchers culled national death records for all people who died from a drug overdose in the United States between 2010 and 2021. By 2021, stimulants had become the most common drug class found in fentanyl-involved overdoses in every U.S. state, the study showed.

The new findings likely reflect intentional co-use such as combining fentanyl and methamphetamine for a "goofball“ or unintentionally using fentanyl and stimulants, Shover said.

It is difficult to determine whether an overdose was intentional via death certificate data. “Fentanyl is so strong that even small errors or misjudgments in quantity or potency can mean a difference between overdose and the usual effect,” she said.

Fentanyl/stimulant overdose deaths disproportionately affect Black and Native American people. The prevalence of stimulant involvement in fentanyl overdose deaths was 73% among Black women aged 65 to 74, and 69% among Black men aged 55 to 65 in the western United States in 2021. By contrast, it was 49% among the general U.S. population in 2021, the study author noted.

There were also distinct geographic patterns seen for fentanyl/stimulant use. In the Northeast, fentanyl tends to be combined with cocaine, while in the southern and western United States, it is most commonly used with methamphetamine.

Turning these statistics around is going to take multi-pronged efforts starting with improving access to medications for opioid use disorder such as buprenorphine, methadone and extended-release naltrexone, Shover said.

“[We must] get naloxone to every overdose, which happens through education and increased access,” she said. Naloxone rapidly reverses the effects of opioid overdose and is the standard treatment for opioid overdose. The U.S. Food and Drug Administration recently approved Narcan, a naloxone nasal spray, for over-the-counter nonprescription use. Not all drugs being mixed with fentanyl respond to naloxone, but greater access will prevent some overdose deaths.

Obtaining medications for opioid use disorder is also easier because doctors no longer need a specific waiver, known as the X-waiver, to prescribe these medications.

Wider use of so-called contingency management for stimulant use disorder can also make a dent in these numbers, Shover said. This type of therapy provides incentives such as gift cards for people living with stimulant use disorder.

Experts on the front lines of the overdose epidemic are not surprised by the new numbers and are worried about what’s coming next.

“The trend continues to get worse, and there is no end in sight,” said Dr. Alex Manini, an emergency medicine doctor at the Icahn School of Medicine at Mount Sinai in New York City. Now, in addition to fentanyl mixed with stimulants, he is seeing people who overdosed on opioids mixed with xylazine and other medications. Also known as “tranq,” xylazine is a non-opiate sedative approved for veterinary use only. Xylazine is not an opioid, and naloxone can’t reverse its effects.

"The lure of combining stimulants such as methamphetamine or cocaine with illicitly manufactured fentanyl is to not only prolong the euphoria but also lengthen the time until withdrawal symptoms develop since fentanyl's effects wear off rapidly," said Dr. Robert Glatter. He is an assistant professor of emergency medicine at Lenox Hill Hospital-Northwell Health in New York City.

“Users are further lured into the fallacy that combining stimulants with fentanyl decreases the risk of overdose and gives them more energy and time to obtain funds to use the substances again," Glatter added.

This is akin to playing Russian roulette, he said.

What’s also clear from the new study is that deaths from fentanyl mixed with stimulants disproportionately strike racial and ethnic minority communities. “We must devote prevention strategies to these affected communities,” Glatter said.

Routine use of fentanyl strips in clinics may be helpful, he noted. These are strips of paper that can detect the presence of fentanyl in all kinds of drugs. “Developing techniques and approaches to monitor for other potentially lethal psychoactive substances such as xylazine is imperative in helping keep the public safe," Glatter said.

What’s more, a plethora of counterfeit colorful pills containing fentanyl and even xylazine is currently flooding the market. “Teens and even children are attracted to the colorful pills because they resemble candy, unaware of the lethal consequences,” Glatter said.

“We must be vigilant and inform parents of teens and children about the risks of polysubstance abuse, including the wide availability of lethal counterfeit pills containing fentanyl combined with dangerous stimulants,” Glatter warned.

J. Aaron Johnson is director of the Institute of Public and Preventive Health at Augusta University in Georgia.

"A law enforcement-driven approach is unlikely to be successful since fentanyl is so potent,” said Johnson. "A small package can be enough to lace thousands of pills and other substances and can be hidden in almost anything.”

The best approach likely combines increased access to fentanyl test strips at safe injection clinics and wider use of Narcan and other medications that treat opioid use disorder, he said.

Unfortunately, the COVID-19 pandemic made this overdose epidemic worse, Johnson said. “It looked like we as a society finally started to get control of the epidemic in 2018 and 2019 when overdose deaths leveled off and even declined slightly in 2019, but then the pandemic reversed those gains, and overdose deaths skyrocketed as people lost jobs, were isolated from loved ones [and] lost access to mental health/substance use services.”

More information

Learn more about how naloxone works at the U.S. Centers for Disease Control and Prevention.

SOURCES: Chelsea Shover, PhD, assistant professor-in-residence, UCLA David Geffen School of Medicine, Los Angeles; Alex Manini, MD, professor, emergency medicine, Icahn School of Medicine, Mount Sinai, New York City; Robert Glatter, MD, assistant professor, emergency medicine, Lenox Hill Hospital-Northwell Health, New York City; J. Aaron Johnson, PhD, director, Institute of Public and Preventive Health, Augusta University, Augusta, Ga.; Addiction, Sept. 14, 2023